Fentanyl composition for nasal administration

ABSTRACT

The treatment of acute pain with a sufficient dosage by intranasal administration of fentanyl results in a time to onset of action comparable to intravenous administration and a significantly faster onset of action than nasal titration of fentanyl. The nasal administration of a sufficient amount of fentanyl to obtain pain relief has lower maximum plasma concentrations comparable to intravenous administration and results in lower rates of adverse events like respiratory depression, nausea and vomiting. Compositions fur use in the method are also disclosed.

FIELD OF INVENTION

[0001] The present invention relates to a pharmaceutical composition foruse in the treatment of acute pain such as breakthrough pain by means ofa non-invasive administration of fentanyl or a pharmaceuticallyacceptable salt thereof, said composition being such that at least 70 μgof fentanyl is delivered in a dosage unit. The method comprisesadministration of a treatment dosage sufficient to treat the acute painwith time to onset of action comparable to intravenous administration.The treatment typically comprises intranasal administration of arelatively concentrated composition of fentanyl citrate. In addition,the invention relates to a pharmaceutical kit comprising a treatmentdosage of fentanyl for nasal administration for treatment of acute paintogether with a delivery system of an analgesic for a continuoustreatment of chronic pain.

BACKGROUND OF THE INVENTION

[0002] Fentanyl is a potent narcotic analgesic with pharmacologicaleffects similar to morphine. Fentanyl is 50 to 100 times more potentthan morphine on a weight basis. Fentanyl is a mu-receptor agonistacting on receptors distributed in the brain, spinal cord and othertissues. Opioids produce both analgesia and sedation. Opiate agonistsappear to prevent the release of beta-endorphin, possibly by alteringthe patients perceived level of pain and anxiety, although the presenceof pain may still be recognised (1).

[0003] Parenteral fentanyl is indicated for anaesthesia, treatingpostoperative pain, and as a premedicant. Transdermal fentanyl is usedfor managing chronic pain in patients requiring opioids. Fentanyllozenge/sucker (Oralet®) is indicated to induce anxiolysis and analgesiaprior to surgery in pediatric and adult patients. Oral transmucosalfentanyl (Actiq®) is indicated for the management of breakthrough cancerpain in adults with malignancies who are already receiving and who aretolerant to opioid therapy for their underlying persistent cancer pain.Fentanyl Oralet® is only indicated for use in a hospital setting as ananaesthetic pre-medication in the operating room setting or to induceconscious sedation prior to a diagnostic or therapeutic procedure inother monitored anaesthesia care settings in the hospital.

[0004] In normal doses, the most common side-effects of morphine andother opioid analgesics are nausea, vomiting, constipation, drowsiness,and confusion. Tolerance generally develops with long-term use.Micturition may be difficult and there may be ureteric or biliary spasm;there is also an antidiuretic effect. Dry mouth, sweating, facialflushing, vertigo, bradycardia, palpitations, orthostatic hypotension,hypothermia, restlessness, changes of mood, hallucinations, and miosisalso occur. These effects tend to occur more commonly in ambulantpatients than in those at rest in bed and in those without severe pain.Raised intracranial pressure occurs in some patients. Muscle rigidityhas been reported following high doses. The euphoric activity ofmorphine and similar compounds has led to their abuse.

[0005] Unlike morphine, fentanyl is reported not to cause significanthistamine release. Transient hypotension may follow intravenousadministration. Muscle rigidity in high doses may occur and may requireadministration of muscle relaxants; caution is advised in patients withmyasthenia gravis.

[0006] It has been shown (4-7) that fentanyl administered intranasallyin doses of 0.027 mg every 5 minutes, as necessary, is effective in therelief of postoperative pain and cancer pain. In this trial the drug wasdelivered in small dilute doses of small amounts of agent at apredetermined interval of 5 minutes.

[0007] Intranasal delivery of low concentrations and low doses offentanyl has been performed. Concentrations and doses have beenmaintained low due to the risk of respiratory depression associated withhigh doses. Demand-adapted titration was considered to be the onlymethod of avoiding the risk of side effects (4-7). Thus, repeateddelivery of a composition of ca. 50 μg/mL of fentanyl was administered.

[0008] Animal data (rabbits) showed rapid occurring absorption by use ofthe nasal route. The nasal route would therefore be suitable for use inpatients requiring rapid relief of severe pain. General advantages ofnasal application aiming at systemic effect are ease ofself-administration, supporting a health-economic argument and theself-care concept. In addition, first pass liver metabolism andgastro-intestinal metabolism is avoided.

[0009] Intravenously, doses of 50 to 150 μg/kg are indicated foranaesthesia in cardiac surgery whereas doses of 50 to 100 μg IM areeffective as a pre-medication and adjunct to regional anaesthesia.Continuous intravenousinfusion of fentanyl 1.5 μg/kg/hour for 24 hourshas been effective in providing postoperative analgesia withoutsignificant respiratory depression in patients who underwenthysterectomy.

[0010] Transdermal doses range from 25 to 100 μg/hr. Initial doses notexceeding 25 μg/hr are recommended (1).

[0011] Oral transmucosal fentanyl citrate is marketed as fentanylOralet® and Actiq® fentanyl lozenge/sucker (fentanyl Oralet®) in dosesof 5 to 15 μg/kg (maximum 400 μg) is indicated to induce anxiolysis andanalgesia prior to surgery for pediatric patients. Adult dosing offentanyl Oralet® is 5 μg/kg, with a maximum dose of 400 μg. Doses ofActiq® for opioid tolerant patients with breakthrough cancer pain rangefrom 200 to 1600 μg. The initial adult dose of Actiq® is 200 μg. Fromthis initial dose, patients should be closely followed and the dosagenot changed until the patient reaches a dose that provides adequateanalgesia using a single Actiq® dosage unit per break-through cancerpain episode.

[0012] The administration of 3 mL of fentanyl citrate 500 μg/mL (318μg/mL fentanyl base) via nebulization was effective in providingpostoperative analgesia in 10 patients who underwent a variety ofsurgical procedures. However, duration of analgesia varied considerablyfrom 5 to 90 minutes. This route of administration is inefficient andlabour intensive and therefore is generally not recommended (1).

[0013] Fentanyl produces analgesia almost immediately followingintravenous administration whereas in lozenge/sucker delivery and oraltransmucosal administration, onset is seen within 15 minutes.

[0014] Fentanyl is metabolised in the liver and excreted in the urineprimarily as metabolites (less than 7% unchanged drug). The half-life offentanyl is 2 to 4 hours. Fentanyl has a distribution half-life of 10minutes in adults and children (1).

SUMMARY OF THE INVENTION

[0015] The invention relates to a novel composition capable ofdelivering an effective dose of an equivalent of fentanyl throughtransmucosal delivery. Intravenous administration of fentanyl hasnumerous pragmatic disadvantages compared to transmucosal administrationas well as resulting in peak plasma concentrations which are related todangerous side effects such as depression of the respiratory system.However, intravenous administration has one major advantage over currenttransmucosal, oral, and pulmonary administration of fentanyl in that thetime-to-onset-of-action of the intravenous administration is muchfaster. Current transmucosal compositions require administration ofseveral dosage units by the pain sufferer in a “titration” methodwherein the sufferer self administrates as many dosage units as requiredto obtain the alleviation of pain, often requiring 4-6 administrations.The consequence of this “titration” administration is a relatively longtime-to-onset-of-action during which the sufferer continues toexperience pain, often acute pain. The present investigators havedeveloped a composition which administers by transmucosal delivery aneffective dosage of an equivalent of fentanyl to alleviate the pain witha time-to-onset-of-action comparable to that of intravenousadministration, notably after a single administration of saidcomposition.

[0016] A first aspect of the present invention therefore relates to apharmaceutical composition comprising fentanyl, or salts thereof, in asuitable solvent at a concentration equivalent to about 0.4 to 75 mg/mLof fentanyl.

[0017] As stated supra, the present composition is delivered as dosageunit having a concentration sufficient so as to achieve a rapid onset ofaction and avoiding the “titration delivery” of the agent. Thus, thedosage unit is also an important aspect of the present invention as it,in one or two delivery operations, must provide sufficient amounts ofthe agent. Thus, a second aspect of the invention relates to a dosageunit comprising fentanyl, or salts thereof, in a suitable solvent,having a concentration equivalent to about 0.4 to 75 mg/mL of fentanyl.

[0018] The use of a composition comprising fentanyl, or salts thereof,for the preparation of a medicament for the treatment of pain in amammal wherein said medicament comprises a concentration equivalent toabout 0.4 to 75 mg/mL of fentanyl, wherein the medicament is formulatedfor transmucosal administration is a further aspect of the invention.

[0019] Alternatively stated, given the amount of the agent is animportant feature of the medicament, the use of a composition comprisingfentanyl, or salts thereof, for the preparation of a medicament for thetreatment of pain in a mammal wherein administration of said medicamentcomprises delivery of one or more dosage units each equivalent to aboutat least 70 μg of fentanyl, wherein said dosage unit is formulated fortransmucosal administration is a still further important aspect of theinvention. As is clear from the above, the medicament is formulated todeliver dosage units with sufficient amounts of the agent. Thus, the useof a composition comprising fentanyl, or salts thereof, for thepreparation of a medicament for the treatment of pain in a mammal,wherein said medicament is formulated for transmucosal administration ofa dosage unit, wherein said dosage unit comprises an amount equivalentto about at least 70 μg of fentanyl is an important aspect of thepresent invention.

[0020] The composition is directed to pain management. An importantaspect of the invention relates to a method for treating, alleviating orlessening pain in an individual comprising the administration of apharmaceutical composition comprising fentanyl, or salts thereof, in adosage unit equivalent to at least 70 μg of fentanyl. Alternativelydefined, this aspect of the invention relates to a method for treating,alleviating or lessening pain in an individual comprising theadministration of a pharmaceutical composition comprising fentanyl, orsalts thereof, wherein said composition has a concentration equivalentto about 0.4 to 75 mg/mL of fentanyl.

[0021] A still further aspect of the invention relates to a method forthe administration of fentanyl or a pharmaceutically acceptable saltthereof to the circulatory system of an individual in need of acute painrelief comprising administration of a treatment dosage comprising 70 μgto 2000 μg fentanyl in a pharmaceutical vehicle for transmucosaldelivery of fentanyl to a mucosal membrane of the individual.

[0022] Pain management using the composition, dosage units or methods ofthe invention may be paired with other technologies to form part ofmulti-component strategy to pain management. This strategy may, forexample, utilise known technologies for the management of chronic painand the present invention for management of pain during acute episodesof pain. Thus, a further aspect of the invention relates to a kitcomprising

[0023] i) composition formulated for the delivery of a dosage unitcomprising 70 μg to 2000 μg of fentanyl, or pharmaceutically acceptablesalts thereof for a continuous treatment of pain in a vehicle fortransmucosal delivery for the treatment of acute pain; and

[0024] ii) an analgesic for continuous treatment of pain.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The term “fentanyl” is intended to relate to fentanyl or apharmaceutically acceptable salt thereof. The term “equivalent to about. . . of fentanyl” is intended to relate to a specified volume,concentration, or amount of fentanyl free base provided by a volume,concentration, or amount of a salt of fentanyl. Thus the specifiedamount relates to the amount of fentanyl free base and not the amount ofthe fentanyl salt, despite the use of the salt in the composition. In amost preferred embodiment, the composition, methods and uses of thepresent invention comprise the use of fentanyl citrate.

[0026] The term “formulated” is intended to relate to the selection ofexcipients, carriers, vehicles, preservatives, stabilising agents and soforth in the preparation of medicament using said composition. The term“formulated” is furthermore intended to relate to the selection of thedevice for delivery of the composition or selection of containmentdevice for administration or storing of the composition.

[0027] The term “dosage unit” relates to the composition administered inone administration by one delivery operation. In the embodiment whereinthe composition is formulated for transmucosal administration by nasaldelivery, a dosage unit is the volume of the composition administered oramount of agent administered by one delivery operation. A deliveryoperation is an operation which delivers a dosage unit. In thisembodiment, a delivery operation is the administration to the nasalcavity of a dosage unit by means of a delivery system, such as a nasalspray or other means known to the person skilled in the art. Suitabledevices are commercially available from e.g. Pfeiffer and Valois. Theterms “dosage” and “treatment dosage” relates to the total amount ofagent or volume of composition applied by means of administration ofdosage units during a treatment. A treatment relates to theadministration of the composition during a single episode of pain, saidepisode lasting until alleviation of pain.

[0028] The term “time-to-onset-of-action” is intended to mean the momentwherein the patient begins to experience pain relief, usually as aresult of sufficient plasma concentrations of fentanyl. Sufficientplasma concentrations to achieve analgesia varies amongst patients,amongst patient classes and types and nature of pain experienced. The“action” in “time-to-onset-of-action” is pain relief.

[0029] The term “duration-of-action” relates to the time throughoutwhich pain relief is experienced by the patient.

[0030] The pharmaceutical composition of the invention comprisesfentanyl, or salts thereof, in a suitable solvent at a concentrationequivalent to about 0.4 to 75 mg/mL of fentanyl. The composition issuitably formulated for transmucosal administration, typically todeliver fentanyl through the nasal mucosa.

[0031] The composition of the invention typically has a concentrationequivalent to about 0.5 to 20 mg/mL of fentanyl, preferably 0.6 to 15mg/mL, 0.7 to 12 mg/mL, more preferably 0.75 to 10 mg/mL of fentanyl,most preferably 0.75 to 8 mg/mL. Suitable compositions have aconcentration equivalent to about at least 0.5 mg/mL of fentanyl, suchas 0.7 mg/mL, such as 0.75 mg/mL, such as about 1 mg/mL, about 1.5,about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5,about 5.5, about 6, about 6.5, about 7, about 7.5, and about 8 mg/mL.

[0032] As stated, the composition is delivered as a dosage unit whereinadministration comprises delivery of one or more dosage units of about10 to 500 μL, such as 10 to 200 μL, preferably about 50 to 150 μL. Inthe embodiment wherein delivery is via the nasal mucosa, a delivery unitcorresponds to the volume provided by a squirt or spray, depending onthe device utilised for delivery of the composition and dosage unit.

[0033] In the event wherein the nasal application exceeds about 200 μl,there may be a risk of loss of the formulation to the larynx or lossthrough the nostrils. Accordingly, the formulation for nasaladministration should preferably not exceed 200 μl. Accordingly, apreferred volume according to the invention includes a volume selectedfrom 10 μl, 25 μl, 50 μl, 75 μl, 100 μl, 150 μl, 200μl, 250 μl, 300 μl,and 350 μl, and 400 μl where the volume may be delivered to bothnostrils if preferred.

[0034] In a preferable embodiment, said composition is formulated fornasal delivery of a dosage unit comprising an equivalent to at leastabout 70 μg of fentanyl, such as 80, 90, or 100 μg, such as 125, 150,200, 250, or 300 μg, such as 350, 400, 450, 500 μg, such as 550, 600,650, 700, 750, 800, 850, 900, or 950 μg, such as 1000, 1050, 1100, 1250,or 1300 μg, such as 1350, 1400, 1450, 1500 μg, such as 1550, 1600, 1650,1700, 1750, 1800, 1850, 1900, or 1950 μg, such as a dosage unitequivalent to 2000 μg of fentanyl.

[0035] Alternatively defined, the composition is formulated fortransmucosal delivery of a dosage unit equivalent to about 70 to 2000 μgof fentanyl, such as 70 to 1800 μg, preferably 70 to 1500 μg, such as 70to 1200 μg, particularly preferably 70 to 1000 μg, more preferably 70 to500 μg, most preferably equivalent to 75 to 300 μg of fentanyl.

[0036] The present invention further relates to a method for theadministration of fentanyl or a pharmaceutically acceptable salt thereofto the circulatory system of an individual in need of acute pain relief.The treatment dosage is such that to be sufficient to treat the acutepain within a narrow time-to-onset-of-action. In order to result in aplasma concentration sufficient to treat acute pain, a treatment dosagewill normally be within a range of at least 70 μg and up to 2000 μgfentanyl. In order to have the fentanyl administered to the circulatorysystem within an acceptable period and without delivering the fentanylby injection, the fentanyl is administered to a mucosal membrane of thepatient in a pharmaceutical vehicle for transmucosal delivery of thefentanyl.

[0037] The sufficient pain relieving dosage may vary between thepatients as well as in the individual patient. For treatment of relativemoderate acute pain, the treatment dosage may comprise at least 70 μgfentanyl, preferably at least 100 μg fentanyl, more preferred at least150 μg fentanyl, such as 200 μg fentanyl. For treatment of more severeacute pain, the treatment dosage comprises at least 250 μg fentanyl,preferably at least 300 μg fentanyl, more preferred at least 400 μgfentanyl, such as 500 μg fentanyl. In cases where the patient suffersfrom heavy acute pain or the patient has developed tolerance to fentanylhigher dosages may be required and administered according to the presentinvention. Such high dosages include treatment dosage comprising 600 μgfentanyl, preferably at least 800 μg fentanyl, more preferred at least1000 μg fentanyl, such as at least 1200 μg fentanyl. Even higher dosagesmay be desired such as treatment dosages of 1300 μg fentanyl, preferablyat least 1400 μg fentanyl, more preferred at least 1500 μg fentanyl,such as 1600 μg fentanyl. The high dosage treatment may involve patientswhich are receive regular treatment with opioid analgesics, and it isbelieved that a few numbers of patients may need treatment dosagecomprising from 1800 to 2000 μg fentanyl.

[0038] As stated, the compositions of the invention for transmucosaldelivery are of a more potent concentration than compositions known tothe person skilled in the art. Thus, treatment dosages effective foralleviating pain are typically achieved by administration comprisingdelivery of not more than two dosage units. In a preferred embodiment,the composition is formulated such that not more than two dosage unitscomprise a treatment dosage. The composition, although being morepotent, significantly reduces the risk of adverse effects such asdepression of the respiratory system, as shown in the Examples.

[0039] The composition is intended for the treatment, alleviation orlessening of acute or breakthrough pain, such as benign acute painepisodes like angina pectoris, colic/biliary pain, trauma, postoperativepain, dental pain, orofacial pain, sympathetic pain syndrome, pancreaticpain, myocardial infarction pain, back pain, cancer pain, pain during orafter change of dressing and pre-operative anesthesia.

[0040] It is an important aspect of the invention that the pain reliefis always obtained very shortly upon administration of fentanyl.Accordingly, the relief of the acute pain should be obtained veryshortly after administration of the first delivery of the dosage unit ortreatment dosage such that the administration of composition has atime-to-onset-of-action of less than 10 minutes, such as less than 9minutes, preferably less than 8 minutes.

[0041] A very important advantage of the present invention is, inaddition to the very short a time-to-onset-of-action, that the painrelief is maintained for at least 30 minutes. Thus, administration ofthe composition has a duration-of-action maintained throughout a periodof at least 30 minutes. Although, in some instances, it is preferablefor the duration-of-action to be maintained throughout a period of atleast 1 hour or at least 1.5 hours upon administration of the treatmentdosage, given acute pain typically only lasts for brief periods, it isoften preferable for the duration of action to be maintained for atleast 30 minutes but throughout a period of not greater than 90 minutes,preferably maintained throughout a period of at least 30 minutes andthroughout a period of not greater than 60 minutes.

[0042] This is a further advantage of the present invention. Thecomposition is able to have a rapid onset-of-action whilst providing asufficiently long duration-of-action but without an unnecessarilyprotracted period of effect.

[0043] The composition has a pseudo “sustained release” effect incomparison to intravenous administration which has a very rapid onset ofaction but with a very short duration of action. The intravenousadministration results in a higher peak plasma concentration offentanyl. The intravenously administered fentanyl results in a peakplasma concentration directly proportional to the amount of fentanyladministered, i.e a high C_(max). Conversely, the “titration”administration of a composition intranasally as described by Striebel(references 4-7) has a slower onset of action and unnecessarily longduration of action.

[0044] The composition, upon administration, typically has abioavailability of no less than 75% that of intravenous administration,preferably no less than 80% of intravenous administration, morepreferably no less than 90% of intravenous administration.Bioavailability may be determined by its AUC, as is known to the personskilled in the art.

[0045] The method of the invention comprises the administration ofdosage units comprising from 15 about 70 to 2000 kg of fentanyl, saidadministration preferably resulting in a C_(max, nasal)/C_(max, iv)ratio which decreases with increasing dosage units delivered of equalamounts of fentanyl, within the treatment dosage range of from about 70to 2000 μg.

[0046] In a further aspect, the composition, dosage unit, use and methodof the invention is characterised by the effect of the treatment on theacute pain as measured as described herein. One way to record painaccording to the invention comprises the measurement of onset of painrelief. Just before administration of the treatment the time is measurede.g. by starting a stopwatch. When the subject is certain of feeling ameaningful pain relief the time is recorded e.g. by stopping thestopwatch. The composition of the invention, upon administration, has apain reduction score in the range of 2 to 7, such as 2, 3, 4, 5, 6, and7, preferably such as 3, 4, 5, and 6, as measured by PID upon deliveryof no more than two dosage units, preferably after delivery of onedosage unit.

[0047] At least 50% of subjects obtaining onset within 15 minutes afteradministration of treatment will be considered a success. Likewise theduration of effect may be measured as the difference between onset ofeffect and the time point where the subject declares the effect to ceaseor the time when the subject takes rescue medication, whatever comesfirst. Duration of pain relief of at least half an hour experienced byat least 50% of the subjects will be considered a success.

[0048] Another measurement is the Pain Intensity (PI) scored on an11-point numeric rating scale (0=no pain, 10=unendurable pain). PI_(i)is the pain intensity at the time point T_(i). The PI_(i) is measured atone or more of the following time points (T_(i)) before treatment(baseline), at the time of meaningful pain relief, every 15 minutesafter administration of treatment for the two first hours, and every 30minutes for the next two hours. A 40% decrease of mean PI within 15minutes after treatment will be considered a success. Naturally othertime points may and intervals may be selected.

[0049] PI₀ is the baseline pain intensity (scored on a scale asdisclosed above) before administration of treatment (at time T₀). PainIntensity Difference (PID) is the PI₀ compared to the pain intensity attime points after the administration of treatment (PI_(i)). A mean PIDof 2 obtained within 15 minutes after administration will be considereda success.

[0050] A further measurement is the area under the PID curve or the Sumof Pain Intensity Difference (SPID), PI being measured at the timepoints disclosed above. A mean 4-hour SPID of 3 will be considered asuccess.

[0051] One method relates to a pain intensity scale as disclosed hereinwherein pain relief is measured as a pain intensity difference (PID) ofat least 30%, such as at least 40% based on a pain score measured closeto the time of the administration PI₀ and a pain score measured at thetime PI_(i) after administration. The time after administration may beselected from the time of one or more of the following times 3 minutes,5 minutes, 7 minutes, 10 minutes, 15 minutes, 20 minutes, and 30 minutesupon administration. These times is used when the purpose of themeasuring is to evaluate the immediate effect of the administration. Ifa measurement of the duration of treatment is desired, the pain reliefis measured as a pain intensity difference (PID) based on a scoremeasured immediately before the administration PI₀ and at the timePI_(i) after administration, the time after administration beingselected from the time 45 minutes, 60 minutes, 75 minutes, 90 minutes,and 120 minutes upon administration. One alternative is to measure aneffect from a given time after administration to a later time, and inthis respect the desired time range is selected individually.

[0052] The pain relief score may be measured in accordance with themethod disclosed herein or on a scale of 1-100% wherein 100% is a paindescribed by the patient as unbearable and 0% is no pain at all. It ispreferred that the score is at least 30% from the start to the maximumanalgesic effect is obtained.

[0053] A further measurement is as explained above the sum of painintensity difference (SPID) based on a score measured immediately beforethe administration PI₀ and at the time PI_(i) after administration, thetime after administration being selected from the time any time asdesired and includes the times as disclosed herein. In a preferredembodiment, the sum of pain intensity difference is measured from atleast 2 values measured during a period of at least 30 minutes,preferably at least during 45 minutes, preferable at least during 60minutes such as during 90 minutes. Furthermore, the sum of painintensity difference may be measured from at least 5 values such as atleast from 7 values, preferable from at least 10 values such as from 11,12 or 13 values.

[0054] The peak plasma concentrations achieved by intravenousadministration of fentanyl are associated with side effects such asdepression of the respiratory system. As shown in FIGS. 6a-6 d, the peakplasma concentrations of the present invention are sufficient to providethe desired effect (as well as being achieved rapidly and sustainedsufficiently long). Thus, the invention further relates to a compositionwherein said administration of the no more than two dosage units has apeak plasma concentration of no less than 5% and no more than 75% of thepeak plasma concentration obtained by intravenous administration of saiddosage unit(s), within the treatment dosage range of from about 70 to2000 μg, preferably a peak plasma concentration of no less than 30% andno more than 75% of the peak plasma concentration obtained byintravenous administration of said dosage unit(s), within the treatmentdosage range of from about 70 to 2000 μg.

[0055] In an interesting aspect of the invention, repeatedadministration of dosage units does not result in increases in peakplasma levels. In intravenous administration, repeated administrationcontinue to elevate the plasma concentrations to undesired high levels.Conversely and advantageously, again possibly due to pseudo sustainedrelease characteristics of the mode of administration, repeatedtransmucosal administration of a dosage unit does not continue toelevate the plasma concentration. Thus, in an interesting embodiment ofthe invention, the method is such that administration of the medicamentresults in a C_(max, nasal)/C_(max, iv) ratio which decreases withincreasing dosage units when comparing equal amounts of fentanyldelivered by both modes of administration (nasal vs. intravenous),within the treatment dosage range of from about 70 to 2000 μg.

[0056] The absorption of fentanyl from mucosal membranes is overall veryfast resulting in good availability of the drug. However, according tothe present invention the nasal mucosal membrane is preferred. Inaddition to the convenience of this administration route for thepatient, the olfactory area of the nose is in close proximity to thebrain. Nevertheless, the treatment dosage may also be administered to amucosal membrane selected from one or more of the buccal mucosalmembranes, the mucosal membrane of the respiratory tract, such as thetracheal mucosa and/or the pulmonary mucosal membrane. In a furtheraspect of the invention the treatment dosage may be administered to morethan one location in the same treatment or the patient may choose theadministration route on an individual basis. Acute pain during night maybe treated with buccal administration if the nasal administrationimplies an irritation of the nose.

[0057] The composition preferably comprises fentanyl as its fentanylcitrate salts.

[0058] fentanyl citrate is easily soluble in water, accordingly asuitable vehicle for transmucosal delivery includes a vehicle comprisingwater, such as a vehicle which comprises as much as about 95%-100%water.

[0059] The composition typically comprises a solvent selected from thegroup comprising isotonic saline, water, polyethylene glycol, orcombinations thereof.

[0060] However, use of a vehicle comprising a suitable polymer,preferably a pharmaceutical vehicle comprising n-ethylene glycol (PEG)may be preferred due to a better sprayability of a liquid comprising apolymer. The PEG is preferably one with relative low molecular weightincluding ethylene glycol represented by the formula H(OCH₂CH₂)_(p)OH,wherein p is an integer in the range of 1 to 14. Such PEG includes PEG200, PEG 300 and PEG 400. Especially PEG 200 and 300 are preferred.

[0061] Other preferred polymers for the pharmaceutical vehicle fortransmucosal delivery of the fentanyl includes one or more substancesselected from n-glycofurols represented by the formula I

[0062] preferably wherein n is an integer in the range of 1 to 8, andmore preferred 1 or 2; or mixtures thereof. The amount of n-ethyleneglycol and/or n-glycofurol contained in the vehicle may be between 0.5to 100 W/W %. The beneficial effects of the polymer include increasedstability of the fentanyl. However, it is preferred that the amount ofn-ethylene glycol and/or n-glycofurol contained in the vehicle is at themost 30% W/w, such as at the most 25% W/W, preferable at the most 15%W/W such at the most 10% W/w, such as the most 5% W/w. The lowestconcentration of the polymer is preferred in formulations with a highconcentration of fentanyl is desired.

[0063] The pharmaceutical vehicle according to the invention alsoincludes the ones wherein the amount of n-ethylene glycol and/orn-glycofurol contained in the vehicle is at the most about 100% W/w,preferable at the most 80% W/w, such as the most 50% W/w. The highestconcentration of the polymer is preferred in formulations with a lowconcentration of fentanyl is desired.

[0064] The increased stability to the fentanyl in the vehicle obtainedby the presence of ethylene glycol and/or n-glycofurol relates to areduced effect on radiation to the fentanyl in the vehicle. The presenceof the polymer is believed to increase the resistance for light stressand possibly also to temperature stress by 1-2.5% per week or about2-10% within one month.

[0065] A further and very important issue according to the invention isthe effect obtained with respect to a decreased adsorption of thefentanyl to the surfaces of the devices used for delivery and/or theutensils used for production. When comparing a vehicle comprising then-ethylene glycol and/or n-glycofurol not comprising the polymericcompound and/or compared with a corresponding vehicle where then-ethylene glycol and/or n-glycofurol is replaced with water, then-ethylene glycol and/or n-glycofurol comprising vehicle provide ahigher degree of active substance. The difference in loss may be within1-20% depending on the specific device.

[0066] A dosage unit of the invention comprises fentanyl, or saltsthereof, in a suitable solvent, at a concentration equivalent to about0.4 to 75 mg/mL of fentanyl. Alternatively defined, a dosage unit isabout 10 to 500 μL, such as about 10 to 200 μL, preferably about 50 to150 μL of the composition of the invention. A dosage unit isadministered to the patient and the amounts of fentanyl administered tothe individual is an important feature of the invention.

[0067] A dosage unit is preferably formulated for transmucosaladministration, preferably wherein transmucosal administration comprisesdelivery of fentanyl through the nasal mucosa.

[0068] As stated, a dosage unit comprises sufficient agent such that,whereupon administration of the composition provides a pain reductionscore in the range of 2 to 7, such as 2, 3, 4, 5, 6, and 7, preferablysuch as 3, 4, 5, and 6, as measured by PID upon delivery of no more thantwo dosage units, preferably after delivery of one dosage unit.

[0069] The method of the invention relates to the treatment, alleviationor lessening of acute or breakthrough pain, such as benign acute painepisodes like angina pectoris, colic/biliary pain, trauma, postoperativepain, dental pain, orofacial pain, sympathetic pain syndrome, pancreaticpain, myocardial infarction pain, back pain, cancer pain, pain during orafter change of dressing and pre-operative anesthesia.

[0070] Alternatively defined, the method comprises the administration offentanyl or a pharmaceutically acceptable salt thereof to thecirculatory system of an individual in need of acute pain relief whereinsaid administration comprises administration of a treatment dosage of nomore than 2 dosage units each comprising 70 μg to 2000 μg of fentanyl ina pharmaceutical vehicle for transmucosal delivery of fentanyl to amucosal membrane of the individual.

[0071] As was implied supra, important aspects of the invention relateto the use of a composition comprising fentanyl, or salts thereof, forthe preparation of a medicament for the treatment of pain in a mammalwherein administration of said medicament comprises delivery of one ormore dosage units each equivalent to about at least 70 μg of fentanyl,wherein said dosage unit is formulated for transmucosal administrationand to a method for treating, alleviating or lessening pain in anindividual comprising the administration of a pharmaceutical compositioncomprising fentanyl, or salts thereof, in a dosage unit equivalent to atleast 70 μg of fentanyl.

[0072] Alternatively defined, the invention relates to the use of acomposition comprising fentanyl, or salts thereof, for the preparationof a medicament for the treatment of pain in a mammal, wherein saidmedicament is formulated for transmucosal administration of a dosageunit, wherein said dosage unit comprises an amount equivalent to aboutat least 70 μg of fentanyl.

[0073] Similarly, the use of a composition comprising fentanyl, or saltsthereof, for the preparation of a medicament for the treatment of painin a mammal wherein said medicament comprises a concentration equivalentto about 0.4 to 75 mg/mL of fentanyl, wherein the medicament isformulated for transmucosal administration and a method for treating,alleviating or lessening pain in an individual comprising theadministration of a pharmaceutical composition comprising fentanyl, orsalts thereof, wherein said composition has a concentration equivalentto about 0.4 to 75 mg/mL of fentanyl are further important aspects ofthe invention.

[0074] High peak plasma concentrations are associated to the seriousside effects related to opioid analgesia. It is thus an object of theinvention to provide a composition and, wherein said administration ofthe no more than two dosage units has a peak plasma concentration of noless than 5% and no more than 75% of the peak plasma concentrationobtained by intravenous administration of said dosage unit(s), withinthe treatment dosage range of from about 70 to 2000 μg, preferably apeak plasma concentration of no less than 30% and no more than 75% ofthe peak plasma concentration obtained by intravenous administration ofsaid dosage unit(s), within the treatment dosage range of from about 70to 2000 μg.

[0075] An important feature of the present invention is that analgesiclevels are reached not by a titration of the composition but byadministration of only one or at most two dosage units. Thus, in apreferred embodiment, administration of no more than two dosage unitsprovides a peak plasma concentration of no less than 5% and no more than75% of the peak plasma concentration obtained by intravenousadministration of said dosage unit(s), at treatment dosages in the rangeof from about 70 to 2000 μg. In a more preferred embodiment,administration of no more than two dosage units provides a peak plasmaconcentration of no less than 30% and no more than 75% of the peakplasma concentration obtained by intravenous administration of saiddosage unit(s), within the treatment dosage range of from about 70 to2000 μg.

[0076] Another aspect of the invention relates to the importance ofreducing the peak plasma concentration of fentanyl without diminishingthe intended analgesic effect. As it has been stated, an importantfeature of the present invention is providing a full analgesic dosagesufficient for alleviating pain by means of one or at most two deliveryoperations comprising administering at most two dosage units, ratherthan the “titration” of stepwise administration of repeated smallerdosages. The present method provides higher plasma concentrations andfaster analgesia. However, in the case of extreme pain, it isanticipated that a treatment dosage may require more than two deliveryoperations of the dosage units of the present invention; the dosageunits comprising at least 70 μg of fentanyl. These repeatedadministrations do not require the patient to await any protractedperiod of time or an effect to take place before a repeatedself-administration. The division of the treatment dosage is primarilyfor the purpose of decreasing the value of the peak concentrationwithout decreasing the treatment dosage. Alternatively, the dosage unitsmay then be customised to meet the needs of the patient so as tocomprise higher doses of fentanyl. In either embodiment, high peakplasma concentrations are intrinsically avoided by the pseudo slow andsustained release characteristics of transmucosal delivery, as shown inFIGS. 1, and 1A-4C.

[0077] Accordingly, in a suitable embodiment delivery of the treatmentdosage may be divided into administration of no more than 4 dosage unitsadministered within no more than 15 minutes, each administrationcomprising at least 70 μg of fentanyl, preferably no more than 3,typically no more than 2, such as 2 or 1. In the embodiment whereinadministration of the treatment dosage comprises administration of morethan 2 dosage units, the last administered dosage may be administered ona time when the effect of the first individual dosage is decreased tosuch a level that the maximum analgesic effect obtainable with thetreatment dosage is lowered substantially. For a maximum analgesiceffect with a given treatment dosage of fentanyl, the divided treatmentdosage is administered within at the most 5 minutes, preferably within 3minutes or 2 minutes. Irrespective of the number of minutes during whichadministration of the treatment dosage of the invention is performed,the important features of a decrease in the maximum peak plasmaconcentration and fast onset-of-action are obtained.

[0078] Accordingly, in one embodiment, the method according to presentinvention relates to a treatment regimen wherein the divided treatmentdosage upon administration of the individual dosage unit quantities ofthe treatment dosage results in a peak plasma concentration which issubstantially lower than the peak plasma concentration of the treatmentdosage administered as a single dosage.

[0079] In an interesting aspect of the invention, repeatedadministration of dosage units does not result in increases in peakplasma levels. In intravenous administration, repeated administrationcontinue to elevate the plasma concentrations to undesired high levels.Conversely and advantageously, again possibly due to pseudo sustainedrelease characteristics of the mode of administration, repeatedtransmucosal administration of a dosage unit does not continue toelevate the plasma concentration. Thus, in an interesting embodiment ofthe invention, the method is such that administration of the medicamentresults in a C_(max, nasal)/C_(max, iv) ratio which decreases withincreasing dosage units when comparing equal amounts of fentanyldelivered by both modes of administration (nasal vs. intravenous),within the treatment dosage range of from about 70 to 2000 μg.

[0080] With respect to nasal administration it is very convenient todivide the treatment dosage into one or more dosages for each nostril.Accordingly, one aspect of the invention relates to a treatment dosagewhich is divided into at the most 3 to 4 individually dosage unitquantities, preferably into 2 or 1 individually dosage unit quantities.

[0081] A suitable administration form of the composition comprising thefentanyl is fentanyl dissolved, dispersed or suspended in a dosage unitquantity volume of 50-400 μl whereby the fentanyl may be administered tothe mucosal membrane of the nose in a dosage unit quantity volume of25-200 μl per nostril. Examples of suitable compositions is disclosed inthe examples and includes a vehicle wherein the treatment dosage offentanyl is comprised in a solution of 10 mg/ml in a vehicle comprising5% PEG.

[0082] The preferred method for transmucosal delivery according to thepresent invention is the nasal route whereby a bioavailability of atleast 50% may be obtained, such as at least 60% and preferably about70%. Thus, a composition preferably has a bioavailability of no lessthan 75% that of intravenous administration, preferably no less than 80%of intravenous administration, more preferably no less than 90% ofintravenous administration.

[0083] As stated, the method of the invention relates to theadministration of fentanyl so as to achieve high plasma concentrations.However, peak plasma concentrations at levels of those achieved byintravenous administration are preferably avoided. Thus, in a preferredembodiment, the method is such that administration of the no more thantwo dosage units has a peak plasma concentration of no less than 5% andno more than 75% of the peak plasma concentration obtained byintravenous administration of said dosage unit(s), within the treatmentdosage range of from about 70 to 2000 μg, preferably a peak plasmaconcentration of no less than 30% and no more than 75% of the peakplasma concentration obtained by intravenous administration of saiddosage unit(s), within the treatment dosage range of from about 70 to2000 μg.

[0084] The treatment regimen according to the invention is relevant forpatients suffering from acute pain such as post-operative pain, painafter accidents and break through pain. The treatment regimen accordingto the invention is especially relevant for patients suffering frombreak through pain despite a suitable continuing analgesic treatment,inter alia where the patient further receives an analgesic administeredin a substantially regular regimen. Such regular regimen may be of anyconventional manner and may include fentanyl or other analgesics. In oneembodiment, the analgesic in the substantially regular regimen is anopioid or opioid analogue or a pharmaceutically acceptable salt thereofincluding fentanyl. The analgesic, such as fentanyl, of thesubstantially regular regimen may be administered orally, by thetransdermal route or by depot devices, or by other conventional meanswell known in the art.

[0085] In one very interesting aspect of the invention, thesubstantially regular regimen includes fentanyl or a pharmaceuticallyacceptable salt thereof administered in a transdermal patch.

[0086] One important aspect of the invention is to provide the patientwith a tool for optimising the treatment of acute pain irrespectively ofan underlying analgesic treatment. By administration of the fulltreatment dosage it is possible to provide the individual patient with arelative plasma concentration of fentanyl corresponding to the painintensity of the individual patient. When the patient recognises thebreakthrough pain or plans activities developing pain with a certaindegree the relevant treatment dosage may be administered in advance orat least before the pain is severe and on a case to case basis. Otherpatients may know the treatment dosage which is sufficient and dividethe dosage as explained above if relevant for avoiding side effects dueto a too high peak plasma concentration of the administered treatment asa single dosage.

[0087] Accordingly, in one aspect the present invention relates to amethod for treating acute pain wherein the patient measures painintensity regularly by use of a score and upon a pain score exceeding apredetermined value administers a treatment dosage of fentanyl relevantfor the individual patient and the pain intensity. In other words thetreatment dosage may be individually correlated to the relative painintensity as measured by the patient himself.

[0088] The use of fentanyl according to the invention includesformulations wherein the treatment dosage of fentanyl is delivered tothe mucosal membrane in the form of a solution, dispersion, emulsion,suspension, bioadhesive and non-bioadhesive gel, powder, micropheres,bioadhesive and non-bioadhesive patches or in other forms suitable fortransmucosal delivery well known in the art including lozenges andlollipops.

[0089] The fentanyl is primarily administered by use of a devicesuitable for delivery of liquid, semi-solid or powder formulations tothe mucosal membrane in question and includes use of drops, sprays,aerosols, insufflators, inhalators and patches.

[0090] The present invention further relates to a pharmaceuticalcomposition comprising a treatment dosage of dosage comprising 70 μg to2000 μg fentanyl or a pharmaceutically acceptable salt thereof in apharmaceutically acceptable vehicle having a total volume of 1-2000 μlor a total weight of 1-2000 μg for use in treatment of acute pain. Thepreferred fentanyl is fentanyl citrate in vehicle selected from water,n-ethylene glycol (PEG) and from n-glycofurol and mixtures thereof. Thepreferred ethylene glycol is represented by the formula H(OCH₂CH₂)_(p)OHwherein p is an integer in the range of 1 to 14 and includes PEGselected from PEG 200 and PEG 300 and 400. PEG 300 and 200 being mostpreferred. The n-glycofurols being represented by the formula I shownherein, wherein n is an integer in the range of 1 to 8, preferable inwhich n is mainly 1 and 2.

[0091] The pharmaceutical composition according to present inventionincludes a composition wherein the amount of n-ethylene glycol and/orn-glycofurol contained in the vehicle is between 0.1 to 100 w/w.

[0092] Vehicles and excipients suitable for transmucosal deliveryinclude salts of bile acids such as glycocholate, taurocholate anddeoxycholate; cyclodextrins; chitosan; polysaccharides; lectins such aslycopersicon esculentum agglutinin, wheat germ agglutinin and urticadioica agglutinin; bacterial invasins; fusidic acid derivatives; sodiumtaurodihydrofusidate (STDHF); phospholipids; lysophosphatidylcholine(LPC); didecanoyl-L-phosphatidylcholine (DDPC); vegetable oils such ascoconut oil, groundnut oil and almond oil; benzyl alcohol; bacitracin;sodium hyaluronate; hyaluronic acid; polyacrylic acid and derivativesthereof; methylcellulose; microcrystalline cellulose (MCC);carboxymethyl cellulose; ethyl(hydroxyethyl)cellulose (EHEC);hydroxypropylmethylcellulose (HPMC); plastoid L50; poloaxmers; propyleneglycols; and fatty acids.

[0093] Pain management using the composition, dosage units or methods ofthe invention may be paired with other technologies to form part ofmulti-component strategy to pain management. This strategy may, forexample, utilise known technologies for the management of chronic painand the present invention for management of pain during acute episodesof pain. Thus, a further aspect of the invention relates to a kitcomprising

[0094] i) composition formulated for the delivery of a dosage unitcomprising 70 μg to 2000 μg of fentanyl, or pharmaceutically acceptablesalts thereof for a continuous treatment of pain in a vehicle fortransmucosal delivery for the treatment of acute pain; and

[0095] ii) an analgesic for continuous treatment of pain.

[0096] In a preferred kit, the analgesic for continuous treatment ofpain is fentanyl or a pharmaceutically acceptable salt thereof in a formsuitable for transdermal delivery such as a patch.

[0097] A further aspect of the invention relates to use of a treatmentdosage of fentanyl or a pharmaceutically acceptable salt thereofcomprising 70 μg to 2000 μg fentanyl in a pharmaceutical vehicle fortransmucosal delivery, for the preparation of a medicament for treatingacute pain in a patient in need thereof by administering said treatmentdosage to a mucosal membrane of the patient.

[0098] For the purposes of pain management, the individual may befurther administered an analgesic. The analgesic may be any known to theperson skilled in the art such as those selected from the groupcomprising gold compounds such as sodium aurothiomalate; non-steroidalanti-inflammatory drugs (NSAIDs) such as naproxen, diclofenac,flurbiprofen, ketoprofen, and ketorolac; opioid analgesics such ascodeine, dextropropoxyphene, dihydrocodeine, morphine, diamorphine,hydromorphone, methadone, pethidine, oxycodone, levorphanol, fentanyland alfentanil, para-aminophenol derivatives such as paracetamol; andsalicylates such as aspirin. In a preferred embodiment, wherein theanalgesic is fentanyl, or salts thereof.

[0099] From the Examples, it can be seen that the fentanyl compositionof the invention, formulated for nasal administration, has very similaranalgesic properties to formulations for intravenous administration interms of relation to pain intensity, pain intensity difference and sumof pain intensity difference. Results indicated that total analgesiaobtained with the two formulations did not differ. These observationsand the benefits of the nasal route of administration make nasalfentanyl a most promising new way of treating pain either used alone oras supplementary pain therapy.

[0100] With regards to time-to-onset-of-action, in obtaining analgesiato acute pain, a quick onset of effect is important. From the Examplesand FIG. 5, it can be seen that the median time to onset in the presenttrial was 1 min after intravenous administration and 7 min after nasaladministration. In real life situations it takes time before anintravenous injection can be prepared and given by a nurse or doctorwhereas nasal administration can be handled by the patients themselvesimmediately after the need of analgesia is recognised. Thus the fastestpain relief may well be obtained after nasal self administration offentanyl.

[0101] With regards to duration-of-action, duration of analgesic effectwas found to be 49 min after intravenous administration and 56 min afternasal administration of the composition of the invention. Duration ofanalgesia after a single intravenous dose (up to 100 μg) has been foundto be 30-60 min (16). After i.m. administration duration may be 1-2hours (16). A recent publication elucidated break-through pain (BTP) inhospice patients in which 72% of the BTP episodes lasted less than 30min (16).

[0102] Although the use of plasma concentrations of fentanyl may beclinically useful, plasma levels do not reflect patient sensitivity tofentanyl and therefore should not be used as a sole determinant ofefficacy or toxicity. C_(max-nasal) in the exploratory populationincreased from 0.7 ng/ml for 75 μg to 1.7 ng/ml for 200 μg fentanyl. Inopioid-naive patients, analgesia has been known to be experienced in therange of fentanyl plasma concentrations of 0.2 to 1.2 ng/mL (16),confirming that this study reached therapeutic analgesic plasmaconcentrations of fentanyl. The smaller C_(max-nasal) may result in amore favourable side effect profile for nasally administered fentanyl inregard to side effects related to plasma concentration.

[0103] Notably, mean T_(max) (the time it takes to reach maximum plasmaconcentrations) in the exploratory population using the composition ofthe present invention, was 12.8 min for nasal and 6.0 min forintravenous administration. However, as can be seen from theillustrative examples of Table 1, even at 75 μg, analgesic levels of 0.2to 1.2 ng/mL (if one basis oneself on (16)) were achieved within 3minutes. A stated however, the median time to onset was 7 min afternasal administration

BRIEF DESCRIPTION OF TABLES AND FIGURES

[0104] Table 1 compares the plasma concentrations of illustrativepatients undergoing treatment with 75 μg of fentanyl by means of nasaladministration to those receiving 75 μg of fentanyl by means ofintravenous administration. Data points are plotted in FIGS. 1A, 1B, and1C.

[0105] Table 2 compares the plasma concentrations of illustrativepatients undergoing treatment with 100 μg of fentanyl by means of nasaladministration to those receiving 100 μg of fentanyl by means ofintravenous administration. Data points are plotted in FIGS. 2A, 2B, 2Cand 2D.

[0106] Table 3 compares the plasma concentrations of illustrativepatients undergoing treatment with 150 μg of fentanyl by means of nasaladministration to those receiving 150 μg of fentanyl by means ofintravenous administration. Data points are plotted in FIGS. 3A, 3B and3C.

[0107] Table 4 compares the plasma concentrations of illustrativepatients undergoing treatment with 200 μg of fentanyl by means of nasaladministration to those receiving 200 μg of fentanyl by means ofintravenous administration. Data points are plotted in FIGS. 4A, 4B and4C.

[0108] Table 5 compares pain intensity (PI) scores and pain intensitydifference (PID) scores of intranasal administration to intravenousadministration at 75 μg of fentanyl of individual patients. PID valuesare plotted in FIG. 6a.

[0109] Table 6 compares pain intensity (PI) scores and pain intensitydifference (PID) scores of intranasal administration to intravenousadministration at 100 μg of fentanyl of individual patients. PID valuesare plotted in FIG. 6b.

[0110] Table 7 compares pain intensity (PI) scores and pain intensitydifference (PID) scores of intranasal administration to intravenousadministration at 150 μg of fentanyl of individual patients. PID valuesare plotted in FIG. 6c.

[0111] Table 8 compares pain intensity (PI) scores and pain intensitydifference (PID) scores of intranasal administration to intravenousadministration at 200 μg of fentanyl of individual patients. PID valuesare plotted in FIG. 6d.

[0112]FIG. 1 illustrates the differences in plasma profiles over time ofthe three compared methods and compositions. Intravenous administrationresults in a sharp peak providing a rapid onset of action. However, theplasma levels quickly decrease as well. The high peak concentrations ofintravenous administration are associated with the adverse side effectsof the treatment. Conversely, the “titration” treatment described in(4-6), provides peak concentrations after a period of time considered tobe too long by some pain sufferers. The time to onset of action is muchlonger than intravenous administration or the method of the invention.The composition and method of the present invention provides relativelyfast onset of action and peak plasma concentrations, as well as havingan extended duration of effect as shown by the slow sloping downwardcurve as opposed to the relatively steep downward curve of intravenousadministration.

[0113]FIGS. 1A, 1B and 1C compare the plasma concentrations ofillustrative subjects undergoing treatment with 75 μg of fentanyl bymeans of nasal administration to those receiving 75 μg of fentanyl bymeans of intravenous administration. High plasma concentrations arereached relatively rapidly by nasal administration with a longerduration of action. Peak plasma concentrations are lower than byintravenous administration.

[0114]FIGS. 2A, 2B, 2C and 2D compare the plasma concentrations ofillustrative patients undergoing treatment with 100 μg of fentanyl bymeans of nasal administration to those receiving 100 μg of fentanyl bymeans of intravenous administration. High plasma concentrations arereached relatively rapidly by nasal administration with a longerduration of action. Peak plasma concentrations are lower than byintravenous administration.

[0115] In FIGS. 3A, 3B and 3C compare the plasma concentrations ofillustrative patients undergoing treatment with 150 μg of fentanyl bymeans of nasal administration to those receiving 150 μg of fentanyl bymeans of intravenous administration. High plasma concentrations arereached relatively rapidly by nasal administration with a longerduration of action. Peak plasma concentrations are lower than byintravenous administration.

[0116]FIGS. 4A, 4B and 4C compare the plasma concentrations ofillustrative patients undergoing treatment with 200 μg of fentanyl bymeans of nasal administration to those receiving 200 μg of fentanyl bymeans of intravenous administration. High plasma concentrations arereached relatively rapidly by nasal administration with a longerduration of action. Peak plasma concentrations are lower than byintravenous administration.

[0117]FIG. 5 graphically illustrates the median time to onset of actionfor the varying doses of fentanyl administered intranasally andintravenously.

[0118]FIGS. 6a, 6 b, 6 c and 6 d depict the PID profiles of individualpatients at 75, 100, 150 and 200 μg of fentanyl, respectively,administered intranasally in comparison to the same dose administeredintravenously.

[0119]FIG. 7 illustrates the analgesic profile of oral p.n. treatment ofbreakthrough pain, depicting the typical pain level during the day for apatient. It also shows the coverage in pain alleviation from the longacting, controlled release morphine twice a day and the fast acting p.n.morphine. As illustrated in FIG. 7, it is obvious that the action of thep.n. morphine is too slow to cover the fast occurring breakthrough pain.

[0120]FIG. 8 illustrates the pain relief obtained by the administrationof a nasal formulation of fentanyl along with controlled releasemorphine. The morphine covers the baseline (chronic) pain, whereas thefast onset-of-action of the intranasal fentanyl provides improved painrelief during the breakthrough pain episodes.

EXAMPLES Example 1 Fentanyl Nasal Formulations, Compositions Example 1.0

[0121] I fentanyl 0.75 mg to 15 mg II sodium chloride 0 to 9 mg IIIdisodium edetate 0 to 4 mg disodium hydrogen phosphate dihydrate 0 to 15mg sodium dihydrogen phosphate dihydrate 0 to 15 mg IV purified orsterile water up to 1 mL

[0122] Fentanyl may be included in the formulation as a salt,appropriately adjusted by weight to achieve the correct concentration offentanyl. Other tonicity-adjusting agents may be used instead of or incombination with sodium chloride such as dextrose, glycerol, sorbitol,mannitol, potassium nitrate and sodium sulphate decahydrate or mixturesthereof. pH may be adjusted to an appropriate level by use of acids andbases such as hydrochloric acid and sodium hydroxide. Other buffer saltsthan the phosphates may be used alone or in combination: citric acid,citrate salts and potassium salts. Sufficient microbiologicalpreservation may be achieved by addition of benzalconium chloride,sodium edetate, disodium edetate, benzyl alcohol, parabenes or acombination thereof.

[0123] Preparation:

[0124] The solid ingredients are dissolved one by one or all at the sametime in water. The formulation is subsequently filled into appropriatemultiple dose or single dose nasal spray devices, which may be equippedwith electronic or mechanical recording and/or lock-out systems.

Example 1.1

[0125] Composition of fentanyl nasal solution 0.75 mg/ml (75 μg/dose) Ifentanyl citrate 1.18 mg II sodium chloride 7.47 mg II disodium hydrogenphosphate dihydrate 2 mg sodium dihydrogen phosphate dihydrate 2 mg IVsterile water up to 1 mL

Example 1.2

[0126] Composition of fentanyl nasal solution 2 mg/mL (200 μg/dose) Ifentanyl citrate 3.14 mg II sodium chloride 7.37 mg III disodiumhydrogen phosphate dihydrate 2 mg sodium dihydrogen phosphate dihydrate2 mg IV sterile water up to 1 mL

Example 1.3

[0127] Composition of fentanyl nasal solution 4 mg/mL (400 μg/dose) Ifentanyl citrate 6.28 mg II sodium chloride 7.21 mg Ill disodiumhydrogen phosphate dihydrate 2 mg sodium dihydrogen phosphate dihydrate2 mg IV sterile water up to 1 mL

Example 1.4

[0128] Composition of fentanyl nasal solution 8 mg/mL (800 μg/dose) Ifentanyl citrate 12.56 mg II sodium chloride 6.89 mg III disodiumhydrogen phosphate dihydrate 2 mg sodium dihydrogen phosphate dihydrate2 mg IV sterile water up to 1 mL

Example 1.5

[0129] Composition of fentanyl nasal solution 10 mg/mL (1000 μg/dose) Ifentanyl citrate 15.70 mg II disodium hydrogen phosphate dihydrate 2 mgsodium dihydrogen phosphate dihydrate 2 mg III sterile water up to 1 mL

EXAMPLE 2 Fentanyl Nasal Formulations and Compositions Example 2.0

[0130] Composition I fentanyl 0.75 mg to 15 mg II sodium chloride 0 to 9mg III disodium edetate 0 to 4 mg disodium hydrogen phosphate dihydrate0 to 4 mg sodium dihydrogen phosphate dihydrate 0 to 4 mg IVpolyethylene glycol 1 to 300 mg V purified or sterile water up to 1 mL

[0131] Fentanyl may be included in the formulation as a salt,appropriately adjusted by weight to achieve the correct concentration offentanyl. Other tonicity-adjusting agents may be used instead of or incombination with sodium chloride such as dextrose, glycerol, sorbitol,mannitol, potassium nitrate and sodium sulphate decahydrate or mixturesthereof. pH may be adjusted to an appropriate level by use of acids andbases such as hydrochloric acid and sodium hydroxide. Other buffer saltsthan the phosphates may be used alone or in combination: citric acid,citrate salts and potassium salts.

[0132] To inhibit or reduce adsorption of fentanyl to polymer materialsused in the nasal spray device, excipients other than polyethyleneglycols (PEG) may be added. Examples of such agents are alcohol,glycofurol, poloxamers, polyoxythylene castor oil derivatives,polysorbates, propylene glycol cyclodextrins, phospholipids and bilesalts.

[0133] Sufficient microbiological preservation may be achieved byaddition of benzalconium chloride, sodium edetate, disodium edetate,benzyl alcohol or parabenes.

[0134] Preparation:

[0135] The solid ingredients are dissolved one by one in a mixture of IVand V. The formulation is subsequently filled into appropriate multipledose or single dose nasal spray devices, which may be equipped withelectronic recording and/or lock-out systems.

Example 2.1

[0136] Composition of fentanyl nasal solution 0.75 mg/mL (75 μg/dose)with 0.1% PEG I fentanyl citrate 1.18 mg II sodium chloride 7.34 mg IIIdisodium hydrogen phosphate dihydrate 2 mg sodium dihydrogen phosphatedihydrate 2 mg IV polyethylene glycol 1 mg V purified or sterile waterup to 1 mL

Example 2.2

[0137] Composition of fentanyl nasal solution 0.75 mg/mL (75 μg/dose)with 5% PEG I fentanyl citrate 1.18 mg II sodium chloride 2.5 mg IIIdisodium hydrogen phosphate dihydrate 2 mg sodium dihydrogen phosphatedihydrate 2 mg IV polyethylene glycol 50 mg V purified or sterile waterup to 1 mL

Example 2.3

[0138] Composition of fentanyl nasal solution 0.75 mg/mL (75 μg/dose)with 10% PEG I fentanyl citrate 1.18 mg II disodium hydrogen phosphatedihydrate 2 mg sodium dihydrogen phosphate dihydrate 2 mg Illpolyethylene glycol 100 mg IV purified or sterile water up to 1 mL

Example 2.4

[0139] Composition of fentanyl nasal solution 0.75 mg/mL (75 μg/dose)with 30% PEG I fentanyl citrate 1.18 mg II disodium hydrogen phosphatedihydrate 2 mg sodium dihydrogen phosphate dihydrate 2 mg IIIpolyethylene glycol 300 mg IV purified or sterile water up to 1 mL

Example 2.5

[0140] Composition of fentanyl nasal solution 10 mg/mL (1000 μg/dose)with 5% PEG I fentanyl citrate 15.70 mg II sodium chloride 0.23 mg IIIdisodium hydrogen phosphate dihydrate 2 mg sodium dihydrogen phosphatedihydrate 2 mg IV polyethylene glycol 50 mg V purified or sterile waterup to 1 mL

EXAMPLE 3

[0141] Nasal Absorption of Fentanyl in Rabbits Formulations Forintravenous administration 250 μg fentanyl citrate/ml 0.9% saline I fornasal administration  4 mg fentanyl citrate/ml 0.9% saline II for nasaladministration  4 mg fentanyl citrate/ml 5% PEG300 III for nasaladministration  4 mg fentanyl citrate/ml 30% PEG300

[0142] Study Design

[0143] The above-mentioned formulations were administered to New Zealandwhite rabbits (n=7) in a cross-over design. The animals were dosedintravenously with a volume of 400 μl (equal to 100 μg fentanyl citrate)injected in a marginal ear vein. Intranasal administration was performedby use of a pipette delivering a volume of 25 μl (equal to 100 μgfentanyl citrate) into one nostril. Blood samples of 500 μl werewithdrawn at predetermined time intervals up to 60 minutes. The sampleswere subsequently centrifuged and the plasma isolated and frozen. Thecontent of fentanyl in the plasma samples was then determined by use ofa radioimmunoassay.

[0144] Calculations

[0145] The area under the plasma concentration-time curve from 0 to 60minutes (AUC) was determined for all formulations. For each nasalformulation, the bioavailability was calculated using equation 1:$\begin{matrix}{{Bioavailabilty} = {{\frac{{AUC}_{nasal}}{{AUC}_{intravenous}} \cdot 100}{\%.}}} & {{Equation}\quad 1}\end{matrix}$

[0146] The time for the peak plasma concentrations to occur (t_(max))was determined by visual inspection of the plasma concentration-timecurves.

[0147] Results

[0148] The mean plasma concentration time profiles for the intravenousformulations and the nasal formulations were measured and the overallpharmacokinetic results obtained are given in the table below.

[0149] Mean plasma concentration-time profiles of 100 μg of fentanylcitrate administered intravenously and intranasally were in formulationsof 0.9% saline, 5% PEG300 and 30% PEG300 (n=7).

[0150] In the table below, the bioavailability (F) and time for peakplasma concentrations (t_(max)) for intranasal administration of threedifferent formulations of fentanyl (n=7) are shown. Range Formulation IFormulation II Formulation III F (%) 45-80 53-80 43-80 t_(max) (minutes)2-5 2-5 2-5

EXAMPLE 4

[0151] Protocol for Clinical Trial according to the Present Invention:

[0152] A pilot, cross-over study to evaluate the tolerability,pharmacokinetic profile, as well as onset, duration and extent of painrelief of two different formulations of fentanyl in patients with postoperative pain after oral surgery.

[0153] Trial Phase: Phase II (Therapeutic Exploratory)

[0154] Objectives:

[0155] The objectives of this study are to establish the tolerability,the pharmacokinetic profile, the onset and duration, and extent of painrelief of intra-nasal application of fentanyl compared to intravenousadministration at four different doses.

[0156] Trial Design:

[0157] This study is designed as a controlled, double blind, doubledummy, 2-way crossover study. The patients are randomised to 4 differentdose levels (obtained through 2 different formulations) in a balancedway.

[0158] Trial Population:

[0159] Patients of both genders, age 18 to 40 years, weight normal, withindication for having both mandibular third molars surgically removed.

[0160] Assessments:

[0161] Baseline Pain Intensity

[0162] The baseline pain must be at least “5” on the 11-point numericrating scale (NRS) to include the patient.

[0163] Pharmacokinetic Assessments

[0164] Blood samples will be drawn at (0, 1, 3, 5, 7, 9, 12, 15, 25, 40,60, 90, 120, 180) minutes after administration of study medication.

[0165] Pharmacokinetic assessments will be made founded on the resultsfrom analysis of fentanyl concentrations in blood samples.

[0166] Pain Intensity

[0167] Pain intensity will be scored on the 11-point numeric ratingscale (NRS). Pain intensity difference and sum of pain intensitydifference will be estimated.

[0168] Onset and Duration of Analgesic Effect

[0169] Onset, duration and time to rescue medication will be measured toobtain evidence of the suitability of fentanyl as treatment forbreak-through pain.

[0170] General Impression

[0171] General impression after each period will be obtained.

[0172] Tolerability of the Test Drugs

[0173] Nasal tolerability, CNS effects, influence on mental state, andperipheral oxygen saturation will be measured.

[0174] Investigational Drug:

[0175] 75 μg fentanyl per dose (blow) and 100 μg fentanyl per dose(blow) for intra-nasal application.

[0176] Four dose levels of fentanyl will be administered: 75 μg, 100 μg,150 μg (75 μg×2, five minutes interval between doses), 200 μg (100 μg×2,five minutes interval between doses).

[0177] Comparator:

[0178] Intravenous 75 μg Fentanyl, and Intravenous 100 μg Fentanyl.

[0179] Four dose levels of fentanyl will be administered intravenously:75 μg, 100 μg, 150 μg (75 μg×2, five minutes interval between doses),200 μg (100 μg×2, five minutes interval between doses).

[0180] Placebo:

[0181] To achieve the blinding a nasal application of isotonic bufferedsaline and an i.v. sterile water will be used.

[0182] Trial Visit Procedures Screening/ First First Second SecondInclusion Operation Control Operation Control Day Day Visit Day visitInformed Consent x Inclusion/ x x X x x Exclusion Criteria's Physical xExamination Past and x x X x x Concomitant Illness Urine sample for x xscreening for drug abuse Urine sample for x x screening for pregnancyBlood samples for x x pharmakokinetic analysis Data on Pain x x Oxygen xx Saturation Tolerability x x Adverse Events x x

[0183] List of abbreviations and definitions of terms used in theprotocol AE: Adverse event CRF: Case Report Form SAE: Serious AdverseEvent GCP: Good Clinical Practice ITT: Intention-to-treat PP:Per-protocol NRS: Numeric rating scale IMAFT: fentanyl CI: Confidenceinterval PI: Pain intensity PID: Pain intensity difference SPID: Sum ofpain intensity difference AUC: Area under the curve C_(max): Peak plasmaconcentration T_(max): Time when peak plasma concentration is obtainedk_(e): Elimination rate constant MRT: Mean residence time HVD: Halfvalue duration T_(≧75%Cmax): Duration of plasma concentration above 75%of C_(max)

[0184] At present, fentanyl is administered as i.v., i.m., transdermalor buccal formulations. This study is designed to investigate thepharmacokinetic, tolerability and pain relieving aspects of intra-nasalapplication of fentanyl. The intra-nasal administration of fentanyl willbe non-invasive and should provide a rapid way of pain relief.

[0185] The term break-through pain generally refers to transitoryexacerbation of pain that occurs on background of otherwise stable painin a patient receiving chronic analgesic treatment such as with anopioid treatment. The golden standard for treating episodes ofbreak-through pain has for many decades been supplementary p.n. doses ofshort acting oral morphine. The nature of cancer pain being dynamicnecessitates adjustment of the dose level of chronic, long-acting opioidaccording to the level of p.n. morphine and the intensity and durationof pain episodes.

[0186] The analgesic profile of plain morphine tablets for p.n. usecomprise an onset of analgesia within ½-1 hour, a peak effect after 1½-2hours and a duration of effect of 4-6 hours. Optimising the treatment ofbreak-through pain must focus on a very fast onset of action, a powerfuland flexible pain relief and a sufficiently short duration to cover onlythe break-through episode, and thereby minimising side effects.

[0187] The analgesic profile of oral p.n. treatment of break throughpain is illustrated by the following drawing of FIG. 7, where thetypical pain level during the day for a patient is illustrated togetherwith an illustration of the pain control treatment divided in thecoverage from the long acting, controlled release morphine twice a day,and the fast acting p.n. morphine. As illustrated in FIG. 7 it isobvious that the action of the p.n. morphine is too slow to cover thefast occurring break-through pain.

[0188] Recently, transdermal fentanyl in a patch formulation(Durogesic®) has gained increasingly popularity due to the ease of useand a tendency towards better tolerability. The use of fentanyl asbasic, long-acting pain treatment in cancer patients calls for the useof the same generic in a formulation designed to cover break-throughpain episodes.

[0189] By a nasal formulation of fentanyl as illustrated in FIG. 8, manyof the features to gain successful treatment of break-through pain isobtained: a very fast onset of action—around 5 minutes—and a flexibilitydue to the possibility of divided doses securing a sufficient dosage ofanalgesia reflecting the need both with respect to intensity and toduration.

[0190] The development of the nasal fentanyl is aiming at treating, forone, cancer patients. This pilot study to confirm the concept isextendable to cancer patients, despite directed in this study topatients in need of analgesic treatment due to pain after oral surgery.The Third molar surgery model has the advantage of being a homogeneouspain model due to the uniformity of patients, procedures, operativetrauma and therefore predictable and stable level of pain withoutconfusing ‘noise’ from the many factors normally influencing the painand wellbeing of cancer patients.

[0191] The dose schedule used in this study is first of all based on therecommendations for i.v./i.m. fentanyl for postoperative pain: 50 to 100μg, repeated to achieve the desired level of analgesia—and secondly onthe published pharmacokinetics of nasal fentanyl with a bioavailabilityof the nasal application of 71% as compared to i.v. fentanyl (9). Alsothe experience from acute pain treatment in theanaesthesiologist-staffed ambulance service ‘Laegeambulancen’ wherefentanyl for more than 5 years has been the drug of choice for paintreatment in starting doses of 100 μg i.v. repeated with 5 to 10 minutesintervals until desired effect. In this setting, doses of up to 400 μgare given to patients suffering from very severe pain. The tolerabilityof this regimen has, retrospectively, been checked in hospital recordsto document the safe use (10).

[0192] Tolerability, onset-of-action and duration-of-action wereassessed by a dose finding approach starting with a low dose of 75 μgand a medium dose of 100 μg. Investigating higher dose levels isachieved by repeating the dose with a interval of five minutes, therebyobtaining the desired fast onset, and in addition a sufficient durationof action (designed to manage the break-through pain episodes of ½-1hour), but avoiding too high a peak plasma concentration.

[0193] A cross-over design is applied to gain bioavailability data. Thetreatment dosages were 75 μg single dose, 75 μg dual dose, 100 μg singledose and 100 μg dual dose.

[0194] Because fentanyl is a narcotic analgesic drug, patients—nothealthy volunteers—have been chosen as trial subjects.

[0195] Objectives

[0196] The objectives of this study are to establish the tolerability,the pharmacokinetic profile, the onset, duration, and extent of painrelief of intra-nasal application of fentanyl compared to i.v.administration at four different doses.

[0197] Trial Design

[0198] This study is designed as a controlled, double-blind, doubledummy, 2 way cross-over study. The patients were randomised to 4different dose levels and 2 formulations in a balanced way.

[0199] Postoperative Procedures

[0200] The patients are asked not to leave the department. If thepatient does not experience pain intensity of at least “5” on the11-point NRS within 4 hours, the patient did not receive study In across over study where the patient receive the same dose but indifferent formulation in each of two periods, the patients serve ashis/her own control—in this case supplying a good calculation of thebioavailability and pharmacokinetic data and comparable pain scores. Thestudy is double-blind in order to obtain objective pain scores.

[0201] Methods and Assessments/Measurements

[0202] Patients experiencing pain intensity of at least “5” at the11-point NRS within 4 hours received study medication (and if necessaryrescue medication). These patients were asked to stay for another fourhours for safety reasons and in order to observe onset and duration ofpain relief and to fill-in the questionnaire part of the CRF regardingthe effect of the study medication. Recordings of pain intensity,tolerability of the study drug, and oxygen saturation were performed atthe following time points:

[0203] before intake of study drug (time=0)

[0204] every 15 minutes after intake of study drug for the first 2 hours

[0205] every 30 minutes for the last 2 hours of the stay at thedepartment.

[0206] Simultaneously blood samples were obtained for pharmacokineticstudies (0, 1, 3, 5, 7, 9, 12, 15, 25, 40, 60, 90, 120, 180) minutesafter administration of study medication.

[0207] Overview of post-operative sampling and recordings: Time afteradministration/ Blood Pain Oxygen minutes sample intensity Tolerabilitysaturation  0 X X X X  1 X  3 X  5 X  7 X  9 X 12 X 15 X X X X 25 X 30 XX X 40 X 45 X X X 60 X X X X 75 X X X 90 X X X X 105  X X X 120  X X X X150  X X X 180  X X X X 210  X X X 240  X X X

[0208] The patient was provided with 2 stopwatches. Both watches werestarted in connection with the administration of study medication. Onewatch was stopped when the patients are certain of the effect of thestudy drug, and the second when the patients experience recurrence ofpain. Pain recurrence is defined as “pain relief is no longermeaningful”. If patients took rescue medication before stopping thesecond stopwatch, the time until rescue medication was used as “time toeffect-end”. The times for “onset-of-action” and “effect-end” wererecorded in the CRF. The time for administrating study medication isrecorded in the CRF. If the study medicine did not give sufficient painrelief the patient is allowed to take rescue medicine (Ibumetin®,Nycomed Danmark) 600 mg, 10 pcs.). The patient was asked to wait atleast 1 hour before taking the extra medicine, if possible. The patientwas allowed to bring the rescue medicine home, and was asked to bringthe remaining rescue medication and/or the empty package back at thecontrol visit. At the end of the observation period the patient scoredthe general impression of the treatment.

[0209] The questionnaire part covers time from intake of trialmedication and the next 4 hours. During the stay at the department,recordings of adverse events, if any, took place

[0210] First Control Visit

[0211] One week after the operation the patient returns for a controlvisit. Intake of rescue and concomitant medication, as well as adverseevents, spontaneous reported and reported after direct questioning, ifany, are recorded in the CRF.

[0212] Second Operation Day

[0213] At least one week after the controls visit a second operation isperformed. The procedure from 1^(st) operative day is repeated.

[0214] Postoperative Procedures

[0215] The procedure from 1^(st) operative day is repeated except thatpatients were treated with the test drug if they need pain relief, alsoif their pain intensity does not reach “5” at the 11-point NRS scale.

[0216] Second Control Visit

[0217] One week after the second operation the patient returns for acontrol visit. The procedures are identical to first control visit.

[0218] Administration and Dosage

[0219] The study medicine must be taken when the patient experiencesmoderate to severe pain after the oral surgery (pain intensity of “5” ormore on the 11-point NRS). The patient received both formulations toachieve the double blind design of the study. Each patient therefore hastwo nasal applications—one in each nostril—with an interval of fiveminutes. Simultaneously, the patients have two i.v. injections of 2.0 mLwith an interval of five minutes. At least the first dose of testmedicine will, depending on randomization, be either fentanyl intranasalor fentanyl intravenous. The placebo intranasal and intravenous is usedas second dose for the two lowest dosage groups.

[0220] Baseline Pain Intensity

[0221] The baseline pain must be at least “5” on the 11-point numericrating scale (NRS) to include the patient.

[0222] Question: “Please tick off the pain intensity on the 11-pointscale where 0 corresponds to “no pain”, and 10 corresponds to“unendurable pain”

[0223] The investigator or nurse enters the times and date of intake ofmedicine in the CRF.

[0224] Pharmacokinetic Assessments

[0225] Blood samples of maximal 4 mL were drawn at the above specifiedtime points (a total of 14 samples, corresponding to maximal 56 mL).Samples were centrifuged under cooling conditions at 5° C., plasma wasseparated and stored at −20° C. Plasma samples were shipped in one batchto the laboratory, adequately packed.

[0226] Details on laboratory procedures were described in the LaboratoryAnalysis protocol. Pharmacokinetic parameters were calculated.

[0227] Onset of Analgesic Effect

[0228] Time to onset of effect (first stopwatch).

[0229] Duration of Analgesic Effect

[0230] Offset of analgesic effect (second stopwatch) was stated in theCRF and duration of effect is defined as the length of the interval fromonset of effect to offset of effect. However, if the patient requiresrescue medication before offset, duration was measured as time fromonset to the time of rescue medication.

[0231] Pain Intensity (NRS)

[0232] Pain intensity is scored on the 11-point NRS scale. Recordingstook place every 15 minutes after intake of study drug for the first 2hours and thereafter every 30 minutes for the last 2 hours stay at thedepartment.

[0233] Pi_(i) is the value of Pain Intensity at time point T_(i)(missing values have been adjusted as described under “Correction ofscores”).

[0234] Pain Intensity Difference (NRS)

[0235] PI₀ is the baseline value of Pain Intensity (at time point T₀).

[0236] PID_(i) is the value of Pain Intensity Difference at time pointT_(i).

PI _(Di) =PI ₀ −PI _(i)

[0237] Sum of Pain Intensity Difference, SPID, 4 hours

[0238] CPID_(i) is the cumulated (time weighted) sum of PID up to thetime point T_(i).

CPID ₁ =PID ₁* (T ₁ −T ₀)

CPID ₂ =CPID ₁ +PID ₂*(T ₂ −T ₁)

CPID _(i) =CPID _(i−1) +PID _(i)*(T _(i) −T _(i−1))

SPID=CPID_(i) for i=N

[0239] General Impression (5-Point Scale, 4 Hours)

[0240] Four hours after intake of the study medication, or at the timeof intake of rescue medication, the patient was asked about his/hergeneral impression of the study drug. This was done on a 5-point VRS asdescribed below.

[0241] Question: “What do you think about the study medication?”

[0242] Possible answers:

[0243] Poor (0); Fair (1); Good (2); Very good (3); and Excellent (4)were stated in the CRFs.

[0244] Tolerability of the Test Drugs

[0245] See below.

[0246] Adverse Events

[0247] See below.

[0248] Correction of Scores

[0249] Duration of Analgesia:

[0250] For duration, the observation point for patients who continue tohave meaningful effect at the end of the observation period isconsidered to be censored.

[0251] Pain Intensity and Pain Relief:

[0252] Patients who dropout due to lack of effect or who take rescuemedication between one and 4 hours after study medication will keep thepain intensity score immediately prior to dropping out/taking rescuemedication, or the baseline value depending on which is worse. The painrelief score was recorded as 0.

[0253] This procedure may underestimate the effect of the drugs butimitates the clinical course. If no treatment is given, the patient'spains normally stay the same or increase, and the patient does notexperience any relief.

[0254] Time to Rescue Medication:

[0255] Patients who do not require rescue medication within 4 hoursafter study drug administration were considered to have censoredobservations. Missing data in general impression were set to missing andwere therefore not be included in the calculations.

[0256] Concomitant illness relates to any illness that is present at thestart of the trial and continues unchanged. Concomitant medicationrelates to any medication other than the trial product that is takenduring the trial, including screening and run-in periods. During theoperation local anesthetics (3% Citanest-Octapressin®), Astra) was used.The study medicine was nasal fentanyl wherein two different dosestrengths of fentanyl for nasal application were used in the fourdifferent treatment groups:

[0257] 750 μg/mL (as fentanyl citrate)

[0258] in a single dose nasal spray device produced by Pfeiffer,delivering a single validated dose of 100 μL, corresponding to a dose of75 μg of fentanyl per dose. Nycomed Pharma performed the manufacturingof the fentanyl solution and filled the devices.

[0259] 1 mp/mL (as fentanyl citrate)

[0260] in a single dose nasal spray device produced by Pfeiffer,delivering a single validated dose of 100 μL, corresponding to a dose of100 μg fentanyl per dose. Nycomed Pharma performed the manufacturing ofthe fentanyl solution and filled the devices.

[0261] Comparative Treatment, Fentanyl i.v.

[0262] One dose strength of fentanyl was used for the comparative doubleblind formulation to be used for i.v. application:

[0263] Fentanyl solution for injection 50 μg/mL (as fentanyl citrate),Haldid®, ampoules of 2 mL, manufactured by Janssen-Cilag. This solutionwas diluted with sterile water, Nycomed Pharma, in order to achieve aninjection volume of 2 mL in all single injections, meaning that the 100μg group will be dosed with pure Haldid® and the 75 μg group received1.5 mL of Haldid® diluted with 0.5 mL sterile water to 2.0 mL injectionvolume.

[0264] Placebo Treatment.

[0265] To achieve the blinding a double dummy technique was applied.Nasal application devices produced by Pfeiffer, filled with isotonicbuffered saline was used as dummies. Nycomed Pharma filled the devices.Likewise, sterile water, Nycomed Pharma was used for dummy blinding asthe second dose of the i.v. treatment in two of the treatment groups.

[0266] Medicine for Analysis

[0267] In order to check shelf-life under trial conditions, 10 nasaldelivery devices of each dose strength and 10 ampoules of test drug werestored together with the trial medicine at the site of investigation,and were analysed by Nycomed, after termination of the study. Storagetemperature must be below 25° C.

[0268] Randomisation and Blinding

[0269] A sealed code with the randomisation number containinginformation about the treatment for the particular subject will besupplied for each subject.

[0270] The patients were randomised in a balanced way, securing an equaldistribution between treatments (intranasal and intravenous) as well asbetween dosage groups (75 μg, 100 μg, 150 μg, and 200 μg).

[0271] The study was double-blind, that is blinded to the patient, thestaff and in addition to the laboratory staff performing the fentanylanalysis, the Data Management and the statistician until analyses arecompleted. As the patients and staff are blinded to the treatment theschedule must be identical for all patients. This is achieved by adouble-dummy blinding technique for the nasal formulation and for thei.v. control as well due to the wish of using an approved and marketedi.v. formulation. The blinding by double-dummy technique can besummarised: Dose Nasal period* I.v. period group 1. dose 2. dose 1. dose2. dose  75 μg fentanyl Placebo nasal fentanyl i.v. Placebo i.v. nasalPlacebo i.v. Placebo i.v. Placebo nasal Placebo nasal 100 μg fentanylPlacebo nasal fentanyl i.v. Placebo i.v. nasal Placebo i.v. Placebo i.v.Placebo nasal Placebo nasal 150 μg fentanyl fentanyl nasal fentanyl i.v.fentanyl i.v. nasal Placebo i.v. Placebo i.v. Placebo nasal Placebonasal 200 μg fentanyl fentanyl nasal fentanyl i.v. fentanyl i.v. nasalPlacebo i.v. Placebo i.v. Placebo nasal Placebo nasal

[0272] All i.v. administrations are prepared the same way: 1.5 mL isalways taken from “1. Ampoule” and 0.5 mL is always taken from “2.Ampoule”. The different doses are achieved as follows: Time “0” doseTime “5 minutes” dose Dose group 1. Ampoule 2. Ampoule 1. Ampoule 2.Ampoule  75 μg Haldid ® Sterile water Sterile water Sterile water 100 μgHaldid ® Haldid ® Sterile water Sterile water 150 μg Haldid ® Sterilewater Haldid ® Sterile water 200 μg Haldid ® Haldid ® Haldid ® Haldid ®

[0273] All adverse events are classified as either serious ornon-serious based on strictly objective definitions.

[0274] Tolerability

[0275] Nasal tolerability, signs and symptoms related to CNS effects offentanyl, and the influence of fentanyl on mental state was recordedseparately. Likewise the peripheral oxygen saturation—as an indicator ofrespiratory depression was recorded. All such signs and symptoms thatare considered adverse events must be noted.

[0276] Tolerability of the Test Drugs

[0277] This trial has a focus on the tolerability of the nasalapplication form, therefore specific questions related to the nasalapplication has been included. All recordings obtained in this sectionmust, if they are categorised as adverse events, additionally berecorded as such. Recordings will take place before intake of study drugand every 15 minutes thereafter for 2 hours, then every 30 minutes forthe last 2 hours stay at the department.

[0278] Nasal Tolerability.

[0279] Please score the following effect on an 11-point NRS where 0corresponds to no effect and 10 to the greatest effect imaginable

[0280] Sore, itching or stinging nose:

[0281] Sore or stinging throat:

[0282] Dry or stuffy nose:

[0283] Runny nose:

[0284] Taste Disturbance:

[0285] CNS Effects

[0286] Please score the below effects on an 11-point NRS:

[0287] Sedation: 0 corresponds to absolutely normal, active lively anddynamic and 10 means completely relaxed, calm, peaceful and tranquil

[0288] Nausea: 0 corresponds to perfectly normal, no nausea and 10 meanscompletely sick, about to vomit

[0289] Mental State

[0290] Please state the drug influence on mental state by a yes/noanswer: Do you feel high?

[0291] Are things around you mere pleasing than usual?

[0292] Is your speech not as loud as usual?

[0293] Do you feel more dreamy than lively?

[0294] Oxygen Saturation

[0295] Peripheral oxygen saturation was measured transcutaneous (Pulseoxymetry with UV detection) and recorded every 15 minutes for the first2 hours post-dose, and thereafter every 30 minutes.

[0296] Statistical Considerations

[0297] The Trial Statistician was responsible for the statisticalanalyses. A sample size calculation relating to the pharmacokineticobjective of the trial shows that the suggested number of patients givesa realistic possibility of detecting the expected difference in AUC. Thedesign of the trial includes 2 administration routes and 4 differentdoses. The power considerations below are based on the assumption ofdose-AUC linearity, which allows for joining of the four dose groups.This leads to a comparison of the two administration routes via a pairedt-test.

[0298] In a previous trial with i.v. administration of fentanyl(ref), anintra patient variability of 29% on the C_(max) parameter was found.Generally it is expected that the variability of C_(max) and AUC are ofthe same magnitude. In the same study there is a difference of 30% inAUC between nasal and i.v. administration.

[0299] Primary Endpoint

[0300] The AUC is chosen as the primary endpoint, as the sample size andpower calculation justify a result that can detect a difference in AUCbetween the formulations in the level of what can be expected.

[0301] Secondary Endpoints:

[0302] Onset of Analgesic Effect.

[0303] The distribution function of time to onset of effect was analysedas a time to onset variable using the Kaplan-Meier product limitestimation procedure with the purpose of giving a graphical presentationof time to onset. The mean time to rescue medication and 90% Cl wascalculated

[0304] Duration of Analgesic Effect

[0305] Median duration of analgesic effect and 90% Cl were calculated.

[0306] Time Until Rescue Medication:

[0307] The distribution function of time to rescue medication forpatients reporting onset of effect were analysed as a time to onsetvariable using the Kaplan-Meier product limit estimation procedure withthe purpose of giving a graphical presentation of tome to onset. Themean time to rescue medication and 90% Cl were calculated

[0308] The amount of rescue medication used were tabulated.

[0309] General impression (5-point scale):

[0310] Proportions of patients in the 5 categories were illustratedgraphically.

[0311] Tolerability of the Test Drugs

[0312] Nasal tolerability (sum of 5 different 11-point scale scorings):

[0313] Results were tabulated and the mean sum and 90% Cl werecalculated CNS effects (sum of 2 different 11-point scale scorings):

[0314] Results were tabulated and the mean sum and 90% Cl werecalculated Influence on mental state (yes/no response to: feeling high,feeling pleased, feeling of low voice, feeling dreamy):

[0315] Results were tabulated and the mean sum of positive responses and90% Cl were calculated

[0316] Peripheral oxygen saturation measured transcutaneous:

[0317] Graphical presentation of the mean saturation alone, incombination with plasma concentration of fentanyl, and together withpain relief and intensity scores were presented.

[0318] Adverse Events

[0319] Because of the exploratory nature of the trial, all comparativeanalyses were conducted on the Per Protocol population.

[0320] Methods of Analysis

[0321] Primary Endpoint

[0322] The pharmacokinetic profiles of the two application forms werecompared by derived variables of fentanyl.

[0323] The following variables were calculated:

[0324] AUC₀₋₄, area under the curve from zero to 4 hours

[0325] C_(max), peak plasma concentration

[0326] T_(max), time to peak plasma concentration

[0327] MRT, mean residence time

[0328] HVD half value duration

[0329] T_(≧75%) C_(max), duration of plasma concentration above 75% ofC_(max) when K_(e), elimination rate constant

[0330] AUC and MRT were calculated using the trapezoidal rule and theAUMC method (11, 12). The parameters AUC and C_(max), will be tested fordose linearity. Where linearity can be assumed, the administrationroutes were compared by a t-test. If not, the comparison takes accountof dose.

[0331] The following formula were used for the extrapolation, where itis possible to estimate k_(e) (n denotes the time for the last datapoint with measurable concentrations):${\frac{C_{p}}{k_{e}}({AUC})},{{{and}\quad \frac{n \times C_{p}}{k_{e}}} + {\frac{C_{p}}{k_{e}^{2}}({AUMC})}}$

[0332] If it is not possible to estimate k_(e) with reasonable precisionin the single patient, a common estimate were used, where the resultssuggest that it is appropriate. Alternatively, the patients wereexcluded from the analysis of the particular parameter. The eliminationrate constant (k_(e)) was determined as the terminal slope of thesemi-logarithmic plasma concentration time curve by linear regression.

[0333] The peak plasma concentration (C_(max)) was the maximum of themeasured concentrations and the time to peak concentration (T_(max)) thecorresponding sample time.

[0334] The half value duration (HVD) (13) was the time interval withplasma concentrations above 50% of C_(max), and correspondingly T_(≧75%)C_(max) was the time interval with plasma concentrations above 75% ofC_(max)

[0335] T_(max) was compared between the administration routes vianon-parametric methods.

[0336] Exploratory analyses is conducted on the pharmacokinetic profilesand on other pharmacokinetic parameters.

[0337] Medicine for Analysis:

[0338] Will be packed simultaneously with the test medicine, eachfentanyl preparation was packed in separate boxes, and was labelledaccordingly.

EXAMPLE 5

[0339] 5.1 Solubility of Fentanyl Citrate in PEG-Water Mixtures at 25°C.

[0340] It was found that the solubility of FC decreased with increasingconcentrations of PEGs. However, pH varied from about 4 in 2.5% PEG toabout 8 in 100% PEG. The solubility in 0.9% saline was about 16 mg/ml.

[0341] Since it was not possible to keep pH at a constant level, it wasdecided to use a phosphate-citrate buffer (pH 6) for furtherexperiments.

Example 5.2

[0342] Solubility of fentanyl citrate in PEG-buffer mixtures, pH 6 at25° C. and 8° C.

[0343] With pH maintained between 5.9 and 6.5 (and therefore fentanylcitrate almost completely ionised), the solubility of FC decreased fromabout 27 mg/ml in pure buffer to about 10 mg/ml with 30% PEG at 25° C.At 8° C. the solubility in 2.5% PEG was about 10 mg/ml and in 100% PEGabout 3 mg/ml.

Example 5.3

[0344] Solubility of fentanyl citrate in PEG-buffer mixtures, pH 6 at25° C. Modified method The solubility method a included a 5-minuteperiod between subsequent additions of solvent, to allow dissolution.Due to the increased viscosity in vehicles containing PEGs, the rate ofdissolution is reduced. This was performed to investigate whether therate of dissolution itself could cause the reduction in solubility of FCobserved in PEG-vehicles. The solubility of FC decreased from 49 mg/mlwith 2.5% PEG300 to about 25 mg/ml with 30% PEG300. The correspondingfigures for the 5-minute method was 19 mg/ml and 8 mg/ml, respectively.

[0345] It was expected that the solubility would generally be higherwith this modified method. More important, the course of the curve wasalmost identical to the original solubility curve thereby indicatingthat the reducing effect of PEGs on solubility is most likely caused bythe solvent itself and not by the analytical method.

[0346] Calculation of Doses

[0347] Assuming a delivery volume of 100 μl, a dose of 1 mg fentanylbase, equivalent to approximately 1.6 mg fentanyl citrate, requires aformulation concentration of about 16 mg/ml. At room temperature, thecorresponding PEG-concentration is about 5% w/w

[0348] Conclusion

[0349] From the data generated it can be concluded that PEG200 andPEG300 decreases the solubility of FC in water and in buffer at pH 6.Without pH-control, PEGs increase pH. The solubility of FC is lower inPEG300 than in PEG200 and reduction of temperature clearly decreases thesolubility of FC. In conclusion, nasal formulations of FC delivering 1mg fentanyl in 100 μl volumes can be achieved using PEG-concentrationsup to 2.5% w/w.

EXAMPLE 6

[0350] Effect of Periods

[0351] Data for the two days of surgery were compared for allPK-variables. Significant differences were found for AUC₀₋₃, C_(max),HVD (PP population) and MRT₀₋₃ (PP population) Also SPID differed forthe first and second day of surgery. AUC₀₋₃ and C_(max) were both lowerin the first period compared to the second. For AUC₀₋₃: 5% lower fornasal, 14% lower for i.v.; for C_(max): 5% for nasal, 42% lower for i.v.In the PP population this period effect was more pronounced, probablydue to fewer patients. For variables with significant period effect,this was taken into account when statistical analyses were performed,i.e. when comparing formulations and doses.

[0352] Primary Endpoint

[0353] AUC₀₋₃

[0354] AUC_(0-3nasal) increased from 34.9 ng×min/ml for 75 μg to 81.9ng×min/ml for 200 μg fentanyl. For i.v. administration the correspondingfigures were 28.0 and 88.3 ng×min/ml. Linear dose-AUC₀₋₃ relationshipswere found for both routes of administration and both populations

[0355] When routes of administration were compared, i.e. the four dosespooled, AUC_(0-3 nasal) was higher than AUC_(0-3-i.v.) withbioavailabilities of 107% and 110% for the exploratory andPP-populations, respectively. The differences between AUC_(0-3-nasal)and AUC_(0-3-i.v.) were not significant (p=0.14 and p=0.085)

[0356] Secondary Endpoints

[0357] AUC_(0-∞)

[0358] AUC_(0-∞-nasal) increased from 67.7 ng×min/ml for 75 μg to 138.6ng×min/ml for 200 μg fentanyl. For i.v. administration the correspondingfigures were 47.0 and 137.3 ng×min/ml (exploratory population). Lineardose-AUC_(0-∞) relationships were found for both routes ofadministration and both populations.

[0359] When routes of administration were compared, i.e. results for thefour doses pooled, AUC_(0-∞-nasal) was higher than AUC_(0-∞-i.v.) withbioavailabilities of 116% and 119% for the exploratory andPP-populations, respectively. The difference between AUC_(0-3-nasal) andAUC_(0-∞-i.v) was significant for the PP but not for the exploratorypopulation (p=0.045 and p=0.071).

[0360] C_(max)

[0361] C_(max)nasal in the exploratory population increased from 0.7ng/ml for 75 μg to 1.7 ng/ml for 200 μg fentanyl. The correspondingresults for the i.v. formulation were 0.9 and 2.6 ng/ml. Lineardose-concentration relationships were found for i.v. administration inboth populations and for nasal administration in the exploratorypopulation.

[0362] When routes of administration were compared, i.e. results for thefour doses pooled, peak concentration of nasal versus i.v. fentanyl was71% for the exploratory population (p=0.016). For the PP population thisfigure was 67% (p=0.013).

[0363] T_(max)

[0364] When routes of administration were compared, i.e. results for thefour doses pooled, mean T_(max) was 12.8 min for nasal and 6.0 min fori.v. administration. The corresponding values for the PP population were13.0 and 5.8 min (p<<0.0001 for both populations.

[0365] MRT₀₋₃

[0366] MRT₀₋₃ varied between 61.8 and 69.7 min There was no dose-MRT₀₋₃relationship for either population. MRT₀₋₃ nasal tended to be higherthan MRT_(0-3-i.v.) for the PP population (p=0.054) but this was not thecase for the exploratory population (p=0.17).

[0367] MRT₀₋₂₈

[0368] MRT₀₋₂₈ varied between 125.6 and 257.4 min. There was no doserelationship and no difference between the two formulations.

[0369] HVD

[0370] HVD_(nasal) varied between 19.0 and 46.4 min whereas results fori.v. administration were between 10.6 and 30.3 min. No doserelationships were seen (p=0.34 exploratory, p=0.17 PP). HVD was 15.2min in the i.v. PP group, i.e. 13 min shorter than in the nasal group(p=0.0002). For the exploratory population this difference was 8 min(p=0.12).

[0371] T_(>75%) C_(max)

[0372] T_(>75% Cmax) varied between 8.2 and 16.6 min after nasaladministration and between 3.4 and 7.7 min after i.v. administration.There was no dose relationship (p=0.20). T_(>75% Cmax) was 6 min shorterafter i.v. than after nasal administration (p=0.0005). For thePP-population the dose relationship was significant and linear for thenasal formulation (p=0.045) whereas there was no dose relationship forthe i.v. formulation (p=0.81). T_(>75% Cmax) was 7 min shorter afteri.v. than after nasal administration (p=0.001) in the PP population.

[0373] K_(e)

[0374] K_(e) varied between 0.0052 and 0.0073 after nasal administrationand between 0.0047 and 0.0076 after i.v. administration. No differencesbetween routes of administration or doses were observed for eitherpopulation.

[0375] Pain Intensity—PI

[0376] For all eight treatment groups the nadir of pain appeared at 15or 30 min. For the smaller doses, the lowest value generally wasrecorded once; for the higher doses up to three times.

[0377] Sum of Pain Intensity Difference—SPID

[0378] No significant differences between administration routes werefound for either population or between doses. The high standarddeviations of SPID₀₋₄ are explained by the calculation method afterintake of rescue medication. When this took place, i.e. approx. 1 hourafter intake of fentanyl, the highest pain intensity score (eitherbaseline or last value before rescue medication) was maintained until 4hours. In order to reduce standard deviations, SPID for 60 min wascalculated. No significant differences were, however, found afterreducing the period of observation to 60 min

[0379] Time to Onset of Analgesic Effect

[0380] Median time to onset of effect was 1 min for i.v. and 7 min fornasal administration with the four doses pooled (p=0.0001). Nodose-response relationship was found (p=0.75 and 0.55) For theexploratory population median time to onset was 2 min for i.v. and 7 minfor nasal administration (p=0.0001).

[0381] The results are illustrated in FIG. 5

[0382] Duration of Analgesic Effect

[0383] Median duration of effect was 49 min for i.v. and 56 min fornasal administration with the four doses pooled (p=0.61) A trend towardssignificant dose-response relationship for nasal administration was seen(p=0.098). For the exploratory population the dose-response relationshipwas significant with a median duration of 47 min for 75 μg and 89 minfor 200 μg (p=0.04)

[0384] The mean scores for pain intensity at onset and offset ofanalgesic effect were at time points 1.7 and 2.3 for onset, 4.1 and 4.7for offset of effect after i.v. and nasal administration, respectively.

[0385] Rescue Medication

[0386] The amount of analgesic rescue medication, i.e. ibuprofen 600 mgand any other analgesics, is summarised below.

[0387] During the first 4 hours after surgery, ibuprofen was taken inall cases but one. The mean dose was 1.1 ibuprofen tablet. The patientsreceived a total of 10 ibuprofen tablets for supplementary analgesictreatment during the week after tooth extraction. The mean intake was8.2 tablets. Other analgesics were taken as well. Paracetamol was theanalgesic most frequently taken.

[0388] The numbers of ibuprofen tablets taken per dose and route duringthe week after surgery was 1.8 tablets less after nasal (mean intake)than after i.v. administration (doses pooled) (p<0.005).

[0389] Time to Rescue Medication

[0390] Median time to rescue medication was 63 min for i.v. and 68 minfor nasal administration (p=0.87). For the nasal route dose-response wasclose to significance in both populations (p=0.081 and 0.051,respectively).

[0391] General Impression

[0392] Scores for general impression increased with dose, i.e.satisfaction with test treatment was more pronounced with the higherdoses. Scores tended to be higher for i.v. than for nasaladministration.

[0393] Efficacy Conclusions

[0394] Pharmacokinetic Variables

[0395] Presentation of pharmacokinetic variables is based on theexploratory population. Linear dose-AUC relationships were found forboth routes of administration. When nasal and i.v. administrations werecompared, differences of AUC₀₋₃ and AUC_(0-∞), were not significant. Thebioavailability of the nasal formulation therefore was interpreted to be100%.

[0396] A linear relationship between dose and C_(max) was found for bothroutes of administration. With the four doses pooled, peak concentrationof nasal versus i.v. fentanyl was 71% whereas mean T_(max) was 12.8 minfor nasal and 6.0 min for i.v. administration.

[0397] Pharmacodynamic Variables

[0398] Presentation of pharmacodynamic variables is based on the PPpopulation. As reflected in SPID, no significant differences inanalgesia between administration routes were found for either populationor between doses.

[0399] Median time to onset of meaningful effect was 1 min for i.v. and7 min for nasal administration with the four doses pooled. Nodose-response relationships were found. For the exploratory populationthe median time to onset was 2 min for i.v. and 7 min for nasaladministration. The i.v. formulation as seen resulted in a faster onsetof pain reduction. This difference was not reflected in the PainIntensity profiles since pain was recorded only at 15 and 30 min afteradministration.

[0400] Median duration of effect was 49 min for i.v. and 56 min fornasal administration. For the exploratory population the dose-responserelationship was significant with a median duration of 47 min for 75 μgand 89 min for 200 μg.

[0401] That median time to rescue medication was 63 min for i.v. and 68min for nasal administration supports the impression that analgesiceffect is comparable for the two routes of administration.

[0402] Scores for general impression increased with dose, i.e.satisfaction with test treatment was more pronounced with the higherdoses. Scores tended to be higher for i.v. than for nasaladministration.

EXAMPLE 7

[0403] Adverse Events

[0404] No serious adverse events were recorded in this trial.

[0405] The percentages of patients reporting adverse events seem fairlyequally distributed across the three lower doses whereas the number ofevents was high in the 200 μg dose group. Vertigo was the mostfrequently reported most of which were in connection to intravenousadministration. Respiratory depression was recorded 6 times, 5 of whichin relation to intravenous administration. Adverse events were codedaccording to the WHO Adverse Reaction Dictionary version 1999.

[0406] In intravenous administration, adverse events such as pain orinflammation at the site of injection are obviously not observed forintravenous administration. At 150 μg administered intravenously,respiratory depression was observed 3 times whereas at said dose,respiratory depression was not observed for intranasal administration.

[0407] Tolerability. Nasal

[0408] Nasal tolerability, i.e. sore, itching or stinging nose, sore orstinging throat, dry or stuffy nose, runny nose and taste disturbancewas identical for nasal and intravenous administration.

[0409] Tolerability. CNS Effects. Sedation and Nausea

[0410] Findings for the two CNS tolerability variables sedation andnausea indicated that sedation was seen after all but two molarextractions. Worsening of nausea was recorded in 3 patients receivingnasal and 6 patients receiving i.v. fentanyl. Nausea scores were higherin the 150 and 200 μg dose groups. Conclusions were similar for cut offtime points 60 and 240 min.

[0411] Tolerability. Mental State

[0412] For the questions: Are you feeling “high”? Is your speech lessloud than usually? Are your surroundings more pleasant than usually?about one fourth of the patients answered Yes. There seemed to be nodifferences between formulations. There was a tendency towards doseresponse relationship for feeling high. Only a few patients responded tothe question Do you feel more like in a dream than awake?

[0413] There were no deaths or serious/significant adverse events.

EXAMPLE 8

[0414] Oxygen Saturation

[0415] Oxygen saturation was the only laboratory variable tested. Thereseemed to be no difference between routes of administration but atendency towards lower oxygen saturation that lasted longer withincreasing fentanyl doses.

[0416] Baseline values ranged from 94 to 100%. Only one patient had 94%as baseline and this value was the lowest recorded for this patient.Excluding this patient, baseline values ranged from 96 to 100%. Thelowest value for individual patients seen during the 240 min periodvaried between 92 and 98%. These low values were seen only once in therespective patients who received 150/200 μg i.v., 200 μg i.v. and100/150/200 μg nasal doses, respectively. The last oxygen saturationvalues at 240 min varied between 96 and 100%.

[0417] Oxygen Saturation

[0418] There seemed to be no difference between routes of administrationbut a tendency towards lower oxygen saturation that lasted longer withincreasing fentanyl doses. This is quite in line with expectations. Itmay be concluded that for this group of healthy patients, oxygensaturation remained satisfactory during the treatment period.

[0419] Discussion

[0420] Trial Model, Design and GCP Compliance

[0421] The pain model—removal of an impacted mandibular third molar—is astandardised model for investigation of analgesic potency of opioids andother analgesics. The model is well documented. It has the benefit ofbeing suitable for use in both sides of the lower jaw allowing across-over design and thereby minimising the variance in pharmacokineticand pharmacodynamic responses. The single dose design used reflects thetherapeutic explanatory nature of this trial. Randomisation anddouble-blind administration of test treatment was used to avoid bias.For ethical reasons a placebo group was not included. I.v. fentanyl waschosen as comparator since bioavailability of the fentanyl formulationswere to be compared.

[0422] Using a university clinic specialised in running this modelfurther had the advantage that it was used to handle, inform and treatpatients in a uniform way. The staff has profound experience in datacollection and ICH-GCP requirements from a substantial number of trialswith this model.

[0423] Discussion of Data Obtained

[0424] The use of fentanyl should be monitored by clinical assessment.The use of plasma concentrations of fentanyl may be clinically useful;however, plasma levels do not reflect patient sensitivity to fentanyland therefore should not be used as a sole determinant of efficacy ortoxicity.

[0425] Fentanyl Concentration Levels

[0426] In opioid-naive patients analgesia has been obtained in the range0.2 to 1.2 ng/mL (16), confirming that this study reached therapeuticanalgesic plasma concentrations of fentanyl.

[0427] C_(max-nasal) in the exploratory population increased from 0.7ng/ml for 75 μg to 1.7 ng/ml for 200 μg fentanyl. The correspondingresults for the i.v. formulation were 0.9 and 2.6 ng/ml. Lineardose-concentration relationships were found for i.v. administration inboth populations and for nasal administration in the exploratorypopulation. The smaller C_(max-nasal) may hint a more favourable sideeffect profile for nasally administered fentanyl in regard to sideeffects related to plasmaconcentration.

[0428] Mean T_(max) in the exploratory population was 12.8 min for nasaland 6.0 min for i.v. administration. The corresponding values for the PPpopulation were 13.0 and 5.8 min. It is reported in literature that timeto peak concentrations after a standardized consumption time of 15minutes for doses of 200, 400, 800, and 1600 micrograms oraltransmucosal fentanyl produced peak concentrations after 20 to 40minutes (16). Further when 3 doses of oral transmucosal fentanyl citrate800 micrograms were given 6 hours apart to 12 healthy volunteers, mediantimes to peak concentration were 24, 22, and 23.5 minutes for therespective doses. The T_(max-nasal) is therefor seen as satisfactory inregard to the comparable alternative fentanyl treatments. The nasallyadministrated fentanyl in this trial reached recognised therapeutic druglevel and demonstrated a shorter time to peak concentration than forActiq.

[0429] Bioavailability

[0430] When routes of administration are compared, the differencesbetween AUC_(0-3-nasal) and AUC_(0-3-i.v.) respectively AUC_(0-∞-nasal)and AUC_(0-∞-i.v.) are not significant. The bioavailability of the nasalformulation is therefor interpreted to be 100%. Some concern has beengiven to the period effect. It has not been possible to elucidate theapparent difference between periods in regard to administration offentanyl or otherwise.

[0431] In publications the bioavailability of other nasal formulationsin different delivery systems has been demonstrated to be around 70%. Adifferent device delivering different sized drops in a maybe lessprecise manner can explain the very low bioavailability in regard to theone obtained in this study. Further, other studies administer dosesseveral time introducing possibility for loss at every dose. Anotheraspect is the capability of fentanyl to adhere to sudden surfaces. It isnot clear whether this fact is is taken into account in the publishedstudies.

[0432] Oral transmucosal formulations is reported to have abloavailability of 50% (16).

[0433] Onset of Effect

[0434] In obtaining analgesia a quick onset of effect is important.Median time to onset in the present trial was 1 min after i.v. and 7 minafter nasal administration. In real life situations it takes time beforean i.v. injection can be prepared and given by a nurse or doctor whereasnasal administration can be handled by the patients themselvesimmediately after the need of analgesia is recognised. Thus the fastestpain relief may well be obtained after nasal self administration offentanyl.

[0435] In the present trial fentanyl was given to “healthy” patients. Itis, however, believed that PK and analgetic variables will be similar inother, e.g. cancer, patients. Onset of effect after nasal administrationwas at least as good as results found after i.m. (7-8 min (16)) and p.o.transmucosal administration (within 15 min, (16))

[0436] Duration of Effect

[0437] Duration of analgesic effect here was found to be 49 min afteri.v. and 56 min after nasal administration. Duration of analgesia aftera single i.v. dose (up to 100 μg) has been found to be 30-60 min (16).After i.m. administration duration may be 1-2 hours (16).

[0438] A recent publication elucidated break-through pain (BTP) inhospice patients in which 72% of the BTP epsodes lasted less than 30 min(16) In these patients morphine tablets with a duration of several hoursmay cause side effects, e.g. nausea and mental incapacity, for a muchlonger period than the pain relief obtained with the tablet was needed.In these patients fentanyl by nasal administration may give the requiredpain relief without causing prolonged side effects. The effect of nasalfentanyl in BTP in cancer patients has recently been demonstrated (15).

[0439] The variety of diseases and conditions causing acute pain allowsno simple assumption as to optimal duration of analgesia. Numerousclinical conditions, however, exist in which self administered efficientpain relief obtained quickly—as with nasal fentanyl—may be valuable.Nasal fentanyl may be given either alone or as supplementary paintherapy. Examples are pain in connection with postoperativemobilization, short-lasting procedures like change of dressings, anginapectoris, gall stones and trauma. For episodes requiring pain relief fora longer period than supplied by a single dose of fentanyl, nasaladministration may be repeated.

[0440] The analgesic properties of the two formulations were presentedas pain intensity, pain intensity difference and sum of pain intensitydifference. Results indicated that total analgesia obtained with the twoformulations did not differ.

[0441] Scores for general impression increased with dose, i.e.satisfaction with test treatment was more pronounced with the higherdoses. Scores tended to be higher for i.v. than for nasaladministration. The higher scores for i.v. may reflect the fact thatboth medications are received when doses are received.

[0442] Safety

[0443] Safety conclusions based on single dose exposure have onlylimited value because steady-state plasma concentrations and possibleaccumulation of drug. will not occur. Thus, the full adverse eventprofile of fentanyl was not investigated here. In future trials, specialattention should be given to the risk of respiratory depression sincehypoventilation may occur throughout the therapeutic range of fentanyl.The risk, however, increases with plasma levels above 2 ng/ml innon-opioid tolerant patients, especially patients with an underlyingpulmonary condition or who receive other drugs causing respiratorydepression (16). Significant respiratory depression has developed withplasma fentanyl concentrations 1-3 nl/ml whereas respiratory effectswere insignificant below 0.7 nl/ml. There is no predictable relationshipbetween plasma fentanyl concentrations and P_(CO2) (16). In opioid-naïvepatients an increase in CNS effects occurred with plasma fentanyl levelsabove 3 ng/ml (16).

[0444] The adverse event profile for fentanyl, however, was consistentwith the adverse events expected for this compound.

[0445] Benefits of Nasal Administration

[0446] Nasal administration of fentanyl offers a range of benefits. Itis ideal for patients with nausea or vomiting, obstipation or impairedgastro-intestinal absorption. The ease of administration will facilitatecompliance in less motivated patients like children and mentallyconfused/disabled patients.

[0447] Nasal fentanyl can be taken by the patients themselves allowingthe comfort of independence from the medical staff. The psychologicalaspect of being independent and knowing that efficient analgesia can beobtained quickly may even reduce the need for medication. Nasaladministration is non-invasive and therefore may minimize the risk ofinfections. Nasal fentanyl may also be a cost efficient alternative inpatient controlled analgesia.

[0448] Indications

[0449] The main indications of nasal fentanyl appear to be BTP in cancerpatients, bedside therapy in postoperative pain, benign acute painepisodes like angina pectoris, gall stones, trauma and change ofdressing. Also pediatric patients may benefit from the easyadministration of nasal fentanyl. A broad range of organisations dealingwith emergency/acute pain situations, e.g. military, fleet, airlines,rescue teams and sport management, may find the efficiency, quick onsetand easy use of fentanyl interesting.

[0450] The pharmacokinetic results compared well with thepharmacokinetic characteristics known for fentanyl. The bioavailabilityof nasal fentanyl did not differ from that of i.v. fentanyl.

[0451] An onset of analgesic effect within minutes as seen in this trialis an important benefit in treating pain. The limited duration of actionof nasal fentanyl of approximately 1 hour may also be a benefit innumerous clinical scenarios.

[0452] The analgesic properties of the two formulations were presentedas pain intensity, pain intensity difference and sum of pain intensitydifference. Results indicated that total analgesia obtained with the twoformulations did not differ. These observations and the benefits of thenasal route of administration make nasal fentanyl a most promising newway of treating pain either used alone or as supplementary pain therapy.

REFERENCES

[0453] 1. World Medical Association Declaration of Helsinki.Recommendations guiding physicians in biomedical research involvinghuman subjects

[0454] 2. MICROMEDEX Healthcare Series NEW Integrated Index™, DrugdexDrug Evaluation: Fentanyl, latest up-date 06/98, Internet version

[0455] 3. Shannon C N, Baranowski A P. Use of opioids in non-cancerpain. Br J Hosp Med 1997; 58: 459-463

[0456] 4. Schwagmeier R, Oelmann T, Dannappel T, Striebel H W. Patientacceptance of patient-controlled intranasal analgesia (PCINA).Anaesthesist 1996; 45: 231-234

[0457] 5. Striebel H W, Koenigs D, Kramer J. Postoperative painmanagement by intranasal demand-adapted fentanyl titration.Anesthesiology 1992; 77: 281-285

[0458] 6. Striebel H W, Kramer J, Luhmann 1, Rohierse-Hohler I, RiegerA. Pharmakokinetische Studie zur intranasalen Gabe von Fentanyl. DerSchmertz 1993; 7: 122-125

[0459] 7. O'Neil G, Paech M, Wood F. Preliminary clinical use of apatient-controlled intranasal analgesia (PCINA) device. AnaesthIntensive Care 1997; 25: 408412

[0460] 8. Personal communication from Høgskilde S. Safety and efficacyexperience from fentanyl usage at ‘Leageambulancen’. April 2000

[0461] 9. Taburet A M, Steimer J L, Doucet D, Singlas E. Le temps deprésence moyen dans I'organisme. Un nouveau paramètre pharmacocinétique?Therapie 1986;41: 1-10

[0462] 10. Yamaoka K, Nakagawa T, Uno T. Statistical moments inpharmacokinetics. J Pharmacokin Biopharm 1978; 6: 547-58

[0463] 11. Meier J, Nüesch E, Schmidt R. Pharmacokinetic criteria forthe evaluation of retard formulations. Eur J Clin Pharmacol 1974; 7:429-32

[0464] 12. Striebel H W, et al. Intranasal fentanyl titration forpostoperative pain management in an unselected population. Anaesthesia1993; 48: 753-7.

[0465] 13. Striebel H W, et al. Patient-controlled intranasal analgesia:a method for noninvasive postoperative pain management. Anesth Analg1996; 83: 548-51.6228/a5/80-g.

[0466] 14. Zeppetella G. An assessment of the safety, efficacy, andacceptability of intranasal fentanyl citrate in the management of cancerrelated breakthrough pain: a pilot study. J Pain Symptom Manage2000;20(4):253-258

[0467] 15. Zeppetella G. Nebulized and intranasal fentanyl in themanagement of cancerrelated breakthrough pain. Palliat Med 2000;14(1):57-58

[0468] 16. MicroMedex Healthcare Services 2001; Volume 108 TABLE 1 75 μgFentanyl subject no. 1 2 3 Nominal Concentration ConcentrationConcentration Time (ng/ml) (ng/ml) (ng/ml) (min) Nasal i.v. Nasal i.v.Nasal i.v. 0 <0.02 <0.02 <0.02 <0.02 <0.02 <0.02 1 <0.02 0.0223 <0.020.665 <0.02 0.165 3 0.0322 1.58 0.107 1.21 0.0290 1.10 5 0.366 0.8260.253 0.756 0.343 0.758 7 0.592 0.756 0.359 0.673 0.686 0.596 9 0.6920.479 0.297 0.527 0.758 0.537 12 0.564 0.311 0.767 0.368 0.658 0.392 150.483 0.321 0.699 0.248 0.528 0.364 25 0.298 0.255 0.388 0.251 0.4080.238 40 0.157 0.189 0.251 0.234 0.247 0.140 60 0.136 0.154 0.215 0.1870.158 0.113 90 0.113 0.131 0.165 0.132 0.154 0.0781 120 0.0882 0.1110.162 0.122 0.120 0.0728 180 0.0796 0.106 0.174 0.109 0.0564 0.0436

[0469] TABLE 2 100 μg Fentanyl 4 5 6 7 Concentration ConcentrationConcentration Concentration (ng/ml) (ng/ml) (ng/ml) (ng/ml) Nasal i.v.Nasal i.v. Nasal i.v. Nasal i.v. <0.02 <0.02 <0.02 <0.02 <0.02 <0.02<0.02 <0.02 <0.02 1.25 <0.02 0.284 <0.02 0.162 <0.02 0.0753 <0.02 2.69<0.02 3.35 0.138 2.79 <0.02 1.52 0.0566 1.64 0.0838 1.36 0.588 1.270.0566 1.01 0.361 1.22 0.255 1.42 0.948 1.20 0.120 0.952 0.565 1.100.520 1.07 1.12 0.938 0.643 0.798 1.01 0.776 0.912 0.735 0.872 0.7550.897 0.519 0.914 0.649 0.661 0.609 0.622 0.618 0.584 0.453 0.689 0.3850.365 0.479 0.437 0.390 0.428 0.281 0.462 0.312 0.358 0.389 0.336 0.3080.303 0.200 0.308 0.297 0.297 0.321 0.300 0.346 0.218 0.161 0.326 0.2050.217 0.189 0.214 0.268 0.183 0.133 0.273 0.176 0.208 0.173 0.206 0.1910.142 0.133 0.132 0.112 0.208 0.197 0.185 0.186 0.0836 0.0698

[0470] TABLE 3 150 μg Fentanyl Subject No. 8 9 10 Nominal ConcentrationConcentration Concentration Time (ng/ml) (ng/ml) (ng/ml) (min) Nasali.v. Nasal i.v. Nasal i.v. i.v. 0 <0.02 <0.02 <0.02 <0.02 <0.02 <0.02<0.02 1 <0.02 <0.02 <0.02 0.0822 <0.02 5.35 0.186 3 0.119 0.0422 <0.020.976 0.0522 2.12 0.738 5 NS 0.370 <0.02 0.688 0.566 1.28 1.03 7 0.2615.07 0.0587 2.96 1.54 4.07 4.13 9 1.33 2.67 0.175 1.50 2.39 2.06 2.08 121.41 1.19 0.464 0.823 2.28 1.44 1.59 15 1.58 0.771 1.06 0.714 1.64 0.9641.14 25 1.12 0.751 0.866 0.547 1.03 0.640 0.893 40 0.78 0.530 0.8570.464 0.627 0.597 0.626 60 0.559 0.489 0.610 0.407 0.44 0.548 0.538 900.418 0.325 0.383 0.359 0.373 0.380 0.371 120 0.267 0.211 0.278 0.2780.333 0.303 0.407 180 0.182 0.170 0.202 0.177 0.264 0.242 0.257

[0471] TABLE 4 200 μg Fentanyl 11 12 13 Concentration ConcentrationConcrentation (ng/ml) (ng/ml) (ng/ml) Nasal i.v. Nasal i.v. Nasal <0.02<0.02 <0.02 <0.02 <0.02 <0.02 0.0291 <0.02 0.602 <0.02 <0.02 0.352 <0.021.96 <0.02 <0.02 0.802 0.0220 1.32 0.0399 0.0622 2.43 0.148 4.62 0.1010.233 1.33 0.930 2.23 0.595 0.802 0.853 3.23 1.41 1.10 0.961 0.657 3.101.03 1.52 0.761 0.479 1.52 0.788 0.854 0.535 0.409 0.819 0.828 0.5880.367 0.374 0.590 0.432 0.542 0.302 0.334 0.478 0.302 0.409 0.292 0.2970.343 0.381 0.193 0.269 0.188 0.263 0.215 0.167

[0472] TABLE 5 75 μg Fentanyl Subject No. Nominal 1 2 3 Time Nasal i.v.Nasal i.v. Nasal i.v. (min) PI PID PI PID PI PID PI PID PI PID PI PID 05 0 3 0 8 0 4 0 6 0 3 0 15 1 4 0 2 5 3 2 2 1 5 0 3 30 3 2 0 0 6 2 4 0 42 0 3 45 4 1 2 0 8 0 4 0 6 0 2 1 60 5 0 3 0 8 0 4 0 6 0 3 0 75 5 0 3 0 80 4 0 6 0 3 0 90 5 0 3 0 8 0 4 0 6 0 3 0 105 5 0 3 0 8 0 4 0 6 0 3 0 1205 0 3 0 8 0 4 0 6 0 3 0 150 5 0 3 0 8 0 4 0 6 0 3 0 180 5 0 3 0 8 0 4 06 0 3 0 210 5 0 3 0 8 0 4 0 6 0 3 0 240 5 0 3 0 8 0 4 0 6 0 3 0

[0473] TABLE 6 100 μg Fentanyl 4 5 6 7 Nasal i.v. Nasal i.v. Nasal i.v.Nasal i.v. PI PID PI PID PI PID PI PID PI PID PI PID PI PID PI PID 7 0 30 5 0 3 0 5 0 4 0 3 0 6 0 1 6 1 2 1 4 1 2 1 4 1 3 0 3 1 5 2 5 6 −3 3 2 21 2 3 3 1 3 0 6 0 3 4 6 −3 4 1 3 0 4 1 4 0 3 0 6 0 5 2 6 −3 5 0 3 0 5 04 0 3 0 6 0 7 0 6 −3 5 0 3 0 5 0 4 0 3 0 6 0 7 0 6 −3 5 0 3 0 5 0 4 0 30 6 0 7 0 6 −3 5 0 3 0 5 0 4 0 3 0 6 0 7 0 6 −3 5 0 3 0 5 0 4 0 3 0 6 07 0 6 −3 5 0 3 0 5 0 4 0 3 0 6 0 7 0 6 −3 5 0 3 0 5 0 4 0 3 0 6 0 7 0 6−3 5 0 3 0 5 0 4 0 3 0 6 0 7 0 6 −3 5 0 3 0 5 0 4 0 3 0 6 0

[0474] TABLE 7 150 μg Fentanyl Subject No. Nominal 8 9 10 Time Nasali.v. Nasal i.v. Nasal i.v. (min) PI PID PI PID PI PID PI PID PI PID PIPID 0 5 0 2 0 5 0 4 0 4 0 5 0 15 0 5 0 2 1 4 0 4 1 3 0 5 30 0 5 0 2 1 42 2 0 4 0 5 45 0 5 1 1 5 0 4 0 1 3 1 4 60 2 3 2 0 6 −1 4 0 2 2 3 2 75 32 2 0 6 −1 4 0 4 0 5 0 90 3 2 2 0 6 −1 4 0 4 0 5 0 105 4 1 2 0 6 −1 4 04 0 5 0 120 5 0 2 0 6 −1 4 0 4 0 5 0 150 5 0 2 0 6 −1 4 0 4 0 5 0 180 50 2 0 6 −1 4 0 4 0 5 0 210 5 0 2 0 6 −1 4 0 4 0 5 0 240 5 0 2 0 6 −1 4 04 0 5 0

[0475] TABLE 8 200 μg Fentanyl 11 12 13 Nasal i.v. Nasal i.v. Nasal i.v.PI PID PI PID PI PID PI PID PI PID PI PID 2 0 6 0 5 0 6 0 5 0 3 0 0 2 15 1 4 1 5 0 5 0 3 0 2 1 5 1 4 2 4 0 5 0 3 1 1 2 4 3 2 4 2 0 5 1 2 3 −1 42 5 0 8 −2 1 4 4 −1 4 −2 4 2 5 0 8 −2 4 1 4 −1 4 −2 6 0 5 0 8 −2 5 0 4−1 4 −2 6 0 5 0 8 −2 5 0 4 −1 4 −2 6 0 5 0 8 −2 5 0 4 −1 4 −2 6 0 5 0 8−2 5 0 4 −1 4 −2 6 0 5 0 8 −2 5 0 4 −1 4 −2 6 0 5 0 8 −2 5 0 4 −1 4 −2 60 5 0 8 −2 5 0 4 −1

1. A pharmaceutical composition comprising fentanyl or salts thereof, ina suitable solvent at a concentration equivalent to about 0.4 to 75mg/mL of fentanyl, said solvent comprises water.
 2. The compositionaccording to claim 1, wherein said composition is formulated fortransmucosal administration.
 3. The composition according to claim 2,wherein the transmucosal administration delivers fentanyl through thenasal mucosa.
 4. The composition according to any one of the precedingclaims, wherein the concentration is equivalent to about 0.5 to 20 mg/mLof fentanyl, preferably 0.6 to 15 mg/mL, 0.7 to 12 mg/mL, morepreferably 0.75 to 10 mg/mL of fentanyl, most preferably 0.75 to 8mg/mL.
 5. The composition according to any one of the preceding claims,wherein the concentration is equivalent to about at least 0.5 mg/mLfentanyl, such as 0.7 mg/mL, such as 0.75 mg/mL, such as about 1 mg/mL,about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5,about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, and about 8mg/mL.
 6. The composition according to any one of the preceding claims,wherein said fentanyl or salts thereof is fentanyl citrate.
 7. Thecomposition according to any one of the preceding claims, wherein thesolvent comprises solvents selected from the group comprising isotonicsaline, water, polyethylene glycol, or combinations thereof.
 8. Thecomposition according to any one of claims 2 to 7 having abioavailability of no less than 50, 60 or 75% that of intravenousadministration, preferably no less than 80% of intravenousadministration, more preferably no less than 90% of intravenousadministration.
 9. A dosage unit comprising fentanyl or salts thereof,in a suitable solvent, having a concentration equivalent to about 0.4 to75 mg/mL of fentanyl and formulated for nasal delivery of an equivalentto about 70 to 2000 μg of fentanyl.
 10. The dosage unit according toclaim 9 formulated for transmucosal administration, preferably whereinthe transmucosal administration delivers fentanyl through the nasalmucosa.
 11. The dosage unit according to any of the claims 9 or 10having a volume of about 10 to 500 μL, such as about 10 to 200 μL,preferably about 50 to 150 μL.
 12. The dosage unit according to any oneclaims 9 to 11 formulated for nasal delivery of an equivalent of atleast about 70 μg of fentanyl, such as 80, 90, or 100 μg, such as 125,150, 200, 250, or 300 μg, such as at least 350, 400, 450, 500 μg, suchas 550, 600, 650, 700, 750, 800, 850, 900, or 950 μg, such as 1000,1050, 1100, 1250, or 1300 μg, such as 1350, 1400, 1450, 1500 μg, such as1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, or 1950 μg, such as anequivalent to about 2000 μg of fentanyl.
 13. The dosage unit accordingto any one of claims 9 to 12, formulated for nasal delivery of anequivalent to about 70 to 1800 μg of fentanyl, preferably 70 to 1500 μg,such as 70 to 1200 μg, particularly preferably 70 to 1000 μg morepreferably 70 to 500 μg, most preferably equivalent to 75 to 300 μg offentanyl.
 14. The dosage unit according to any one of claims 9 to 13,wherein the concentration Is equivalent to about 0.5 to 20 mg/mL offentanyl, preferably 0.6 to 15 mg/mL, 0.7 to 12 mg/mL, more preferably0.75 to 10 mg/mL of fentanyl, most preferably 0.75 to 8 mg/mL.
 15. Thedosage unit according to any one of claims 9 to 14, wherein theconcentration is equivalent to about at least 0.5 mg/mL fentanyl, suchas 0.7 mg/mL, such as 00.75 mg/mL, such as about 1 mg/mL, about 1.5,about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5,about 5.5, about 6, about 6.5, about 7, about 7.5, and about 8 mg/mL.16. The dosage unit according to any one of claims claim 9 to 15,wherein said fentanyl or salts thereof is fentanyl citrate.
 17. Thedosage unit according to any one of claims 9 to 16, wherein the solventcomprises solvents selected from the group comprising isotonic saline,water, polyethylene glycol, or combinations thereof.
 18. The dosage unitaccording to any one of claims 10 to 17, having a bioavailability, asdetermined by its AUC, of no less than 50, 60 or 75% that of intravenousadministration, preferably no less than 80% of intravenousadministration, more preferably no less than 90% of intravenousadministration.
 19. Use of fentanyl or salts thereof, for thepreparation of a medicament for the treatment of pain in a mammalwherein said medicarnent comprises a concentration equivalent to about0.4 to 75 mg/mL of said fentanyl in a solvent comprising water; andwherein the medicament is formulated for transmucosal administration.20. Use of fentanyl or salts thereof, for the preparation of amedicament for the treatment of pain in a mammal, wherein saidmedicament is formulated for nasal administration of a dosage unit; andwherein said dosage unit comprises an amount equivalent to about atleast 70 μg of entanyl.
 21. The use according to any one of the claims19 or 20, wherein the medicament comprises a concentration equivalent toabout 0.5 to 20 mg/mL of fentanyl, preferably 0.6 to 15 mg/mL, 0.7 to 12mg/mL, more preferably 0.75 to 10 mg/mL of fentanyl, most preferably0.75 to 8 mg/mL.
 22. The use according to any one of claim 19 to 21,wherein the concentration is equivalent to about at least 0.5 mg/mLfentanyl, such as 0.7 mg/mL, such as 0.75 mg/mL, such as about 1 mg/mL,about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5,about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, and about 8mg/mL.
 23. The use according to any one of claims 19 to 22, wherein saidadministration comprises the delivery of a dosage unit of about 10 to500 mL, such as about 10 to 200 μL, preferably about 50 to 150 μL 24.The use according to any one of claims 19 to 23, wherein saidadministration comprises the delivery of a dosage unit each equivalentto at least about 80 μg of fentanyl, such as 90, or 100 μg, such as 125,150, 200, 250, or 300 μg, such as at least 350, 400, 450, 500 μg, suchas 550, 600, 650, 700, 750, 800, 850, 900, or 950 μg, such as 1000,1050, 1100, 1250, or 1300 μg, such as 1350, 1400, 1450, 1500 μg, such as1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, or 1950 μg, such as anequivalent to about 2000 μg of fentanyl.
 25. The use according to anyone of claims 19 to 24, wherein said administration comprises thedelivery of a dosage unit each equivalent to about 70 to 2000 μg offentanyl, such as 70 to 1800 μg, preferably 70 to 1500 μg, such as 70 to1200 μg, particularly preferably 70 to 1000 μg, more preferably 70 to500 μg, most preferably equivalent to 75 to 300 μg of fentanyl.
 26. Theuse according to any of claims 19 to 25, wherein said medicament isformulated for nasal delivery.
 27. The use according to any one ofclaims 19 to 26, wherein said administration comprises delivery of notmore than 2 dosage units, such as 1 or 2 dosage units.
 28. The useaccording to any one of claims 19 to 27 for pain management, and for thetreatment, alleviation or lessening of acute or breakthrough pain, suchas acute pain episodes like angina pectoris, colic/biliary pain, trauma,postoperative pain, dental pain, orofacial pain, sympathetic painsyndrome, pancreatic pain, myocardial infarction pain, cancer pain, backpain, pain during or after change of dressing and pre-operativeanesthesia.
 29. The use according to any one of claims 19 to 28, whereinsaid administration results in a time-to-onset-of action of less than 10minutes, such as less than 9 minutes, preferably less than 8 minutes.30. The use according to any one of claims 19 to 29, wherein saidadministration results in a duration-of-action maintained throughout aperiod of at least 30 minutes.
 31. The use according to any one ofclaims 19 to 30, wherein said administration has a a duration-of-actionmaintained throughout a period of at least 30 minutes and throughout aperiod of not greater than 90 minutes, preferably maintained throughouta period of at least 30 minutes and throughout a period of not greaterthan 60 minutes.
 32. The use according to any one of claims 19 to 31,wherein administration of said composition results in a bioavailability,as determined by its AUC, of no less than 50 or 60 or 75% that ofintravenous administration, preferably no less than 80% of intravenousadministration, more preferably no less than 90% of intravenous,administration
 33. The use according to any one of claims 19 to 32,wherein said administration results in a pain reduction score in therange of 2 to 7, such as 2, 3, 4, 5, 6, and 7, preferably such as 3, 4,5, and 6, as measured by Pain Intensity Difference (PID) upon deliveryof no more than two dosage units, preferably after delivery of onedosage unit.
 34. The use according to any one of claims 19 to 33,wherein said administration of the no more than two dosage units has apeak plasma concentration of no less than 5% and no more than 75% of thepeak plasma concentration obtained by intravenous administration of saiddosage unit(s), within the treatment dosage range of from about 70 to2000 μg, preferably a peak plasma concentration of no less than 30% andno more than 75% of-the peak plasma concentration obtained byintravenous administration of said dosage unit(s), within the treatmentdosage range of from about 70 to 2000 μg.
 35. The use according to anyone of claims 19 to 34, wherein said administration results in aC_(max, nasal)/C_(max, iv) ratio which decreases with increasing dosageunits delivered of equal amounts of fentanyl, within the treatmentdosage range of from about 70 to 2000 μg.
 36. The use according to anyone of claims 19 to 35, wherein the individual further receives ananalgesic.
 37. The use according to any one of claims 19 or 20, whereinthe analgesic is fentanyl, or salts thereof.
 38. A method for treating,alleviating or lessening pain in an individual comprising nasaladministration of fentanyl or salts thereof, in a dose equivalent to atleast 70 μg of fentanyl.
 39. The method according to claim 38, whereinsaid administration comprises the delivery of a dosage equivalent to atleast about 80 μg of fentanyl, such as 90, or 100 μg, such as 125, 150,200, 250, or 300 μg, such as at least 350, 400, 450, 500 μg, such as550, 600, 650, 700, 750, 800, 850, 900, or 950 μg, such as 1000, 1050,1100, 1250, or 1300 μg, such as 1350, 1400, 1450, 1500 μg, such as 1550,1600, 1650, 1700, 1750, 1800, 1850, 1900, or 1950 μg, such as anequivalent to about 2000 μg of fentanyl.
 40. The method according to anyone of claims 38 or 39, wherein said administration comprises thedelivery of a dosage equivalent to about 70 to 2000 μg of fentanyl, suchas 70 to 1800 μg, preferably 70 to 1500 μg, such as 70 to 1200 μg,particularly preferably 70 to 1000 μg, more preferably 70 to 500 μg,most preferably equivalent to 75 to 300 μg of fentanyl.
 41. The methodaccording to any one of claims 38 to 40, wherein said administrationcomprises the delivery of one or more dosages of about 10 to 500 μL,such as about 10 to 200 μL, preferably about 50 to 150 μL.
 42. Themethod according to any one of claims 38 to 41, wherein the pain isselected from the group consisting of acute or breakthrough pain, suchas acute pain episodes like angina pectoris, colic/biliary pain, trauma,postoperative pain, dental pain, orofacial pain, sympathetic painsyndrome, pancreatic pain, myocardial infarction pain, back pain, cancerpain, pain during or after change of dressing, and pre-operative pain.43. The method according to any one of claims 38 to 42, wherein saidtreating, alleviating or lessening of pain comprises the administrationof not more than two dosage units.
 44. The method according to any oneof claims 38 to 43, wherein said administration results in atime-to-onset-of-action of less than 10 minutes, such as less than 9minutes, preferably less than 8 minutes.
 45. The method according to anyone of claims 38 to 44, wherein said administration results in aduration-of-action maintained throughout a period of at least 30minutes.
 46. The method according to any one of claims 38 to 45, whereinsaid administration has a a duration-of-action maintained throughout aperiod of at least 30 minutes and throughout a period of not greaterthan 90 minutes, preferably maintained throughout a period of a least 30minutes End throughout a period of not greater then 60 minutes.
 47. Themethod according to any one of claims 38 to 46, wherein administrationof said composition results in a bioavailability, as determined by itsAUC, of no less than 50, 60, 75% that of intravenous administration,preferably no less than 80% of intravenous administration, morepreferably no less than 90% of intravenous administration
 48. The methodaccording to any one of claims 38 to 47, wherein said administrationresults in. a pain reduction score in the range of 2 to 7, such as 2, 3,4, 5, 6, and 7, preferably such as 3, 4, 5, and 6, as measured by PIDupon delivery of no more than two dosage units, preferably afterdelivery of one dosage unit.
 49. The method according to any one ofclaims 38 to 48, wherein said administration of the no more than twodosage units has a peak plasma concentration of no less than 5% and nomore than 75% of the peak plasma concentration obtained by intravenousadministration of said dosage unit(s), within the treatment dosage rangeof from about 70 to 2000 μg, preferably a peak plasma concentration ofno less than 30% and no more than 75% of the peak plasma concentrationobtained by intravenous administration of said dosage unit(s), withinthe treatment dosage range of from about 70 to 2000 μg.
 50. The methodaccording to any one of claims 38 to 49, wherein said administrationresults in a C_(max, nasal)/C_(max, iv) ratio which decreases withincreasing dosage units delivered of equal amounts of fentanyl., withinthe treatment dosage range of from about 70 to 2000
 51. The methodaccording to any one of claims 38 to 50, wherein the individual furtherreceives an analgesic.
 52. The method according to any one of claims 38to 51, wherein the analgesic is fentanyl, or salts thereof.
 53. A methodfor nasal administration of fentanyl or a salt thereof to thecirculatory system of an individual in need of acute pain reliefcomprising administration of a treatment dosage comprising 70 μg to 2000μg of said fentanyl in a pharmaceutical vehicle to said individual. 54.A method according to any claim 53, wherein the treatment dosage isadministered to the nasal mucosal membrane.
 55. A method according toany one of claims 53 or 54, wherein the pharmaceutical vehicle compriseswater.
 56. A method according to any one of claims 53 to 55, wherein thepharmaceutical vehicle comprises n-ethylene glycol (PEG).
 57. A methodaccording to claim 56, wherein the ethylene glycol is represented by theformula H(OCH₂CH₂)_(p)OH, wherein p is an integer in the range of 1 to14, such as 1, 2, 3, 5, 5, 6, 7, 8, 9, 10, 11, 12, 13, or
 14. 58. Amethod according to claim 56, wherein the PEG is selected from PEG 200and PEG
 300. 59. The method according to any one of claims 53 to 58,wherein the vehicle comprises one or more substances selected fromn-glycofurols represented by the formula I

wherein n is an integer in the range of 1 to 8, preferably in the range1 to 6, such as 1 to 4, such as 1, 2, 3, and 4, preferably 1 and
 2. 60.A kit comprising i) a dosage unit formulated for the nasal delivery of70 μg to 2000 μg of fentanyl or a salt thereof for a continuoustreatment of pain in a vehicle for transmucosal delivery for thetreatment of acute pain; and ii) an analgesic for continuous treatmentof pain.